April 1969

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					                                       INDIAN JOURNAL OF TUBERCULOSIS
                                                      Official organ of the
                                                Tuberculosis Association of India

Editor: Dr.                            Vol. XVI: No. 2                                 April 1969
P.K. Sen
                                       Editorial : Planning, Conduct and Evaluation of
Dr. M.D. Deshmukh
Dr. N.L. Bordia                        Research Studies                                      ... 33
                                       Award of T.A.I. Gold Medal                           ... 35
Associate Editors
D . H.B. Dingley                       Planning of Research Studies
Dr. S.P. Pamra                           —S.S. Nair                                         ... 37

                                       Planning, Conduct and Evaluation of Controlled
                                       Clinical Trials
                                         —S. Radhakrishna                                   …42
                                       Planning and Conduct of Epidemiological Surveys
                                         —G.S. Acharyulu                                    ... 47

                                       Analysis and Presentation of Data
                                        — G.P. Mathur                                       ... 51
                                       Agar Electrophoresis of Serum Proteins in Pulmo-
                                       nary Tuberculosis
                                         —K.L. Agrawal, S. Narasimha Rao and D.P. Agrawal    ... 54

                                       Ethionamide and Isoniazid in the Middle-aged
                                       and the Elderly Patients
                                         —R.K. Narang                                       ... 60
Published quarterly in                 A Comparative Clinical Evaluation of the Role of
the months of January,                 Thiaocetazone and PAS in the Management of
April, July and October.               Pulmonary Tuberculosis
                                         —B.K. Khanna                                       ... 64
Annual Subscription :
Rs. 15/-. £/21/-, $ 3.

Single copy:
Rs.4.00                                           News & Notes        ** Astracts

                                                 * * *

                    Published on behalf of the Tuberculosis Association of India, by
                    the Secretary-General, 3, Red Cross Road, New Delhi-1
          Procedures For Publication Of
               Conference Papers
        The Sub-Committee appointed by the Technical
    Committee of the Association have Lald down
    following procedures regarding publication of
    papers presented at the National Conference on
    TB and Chest Diseases :—

       (1) Papers approved by the Technical Com
    mittee for presentation at the National Conference
    be published in the Proceedings of the Conference.

        (2) Papers presented at the National Con
    ference can be reproduced in full or part thereof in
    the Indian Journal of Tuberculosis and the author
    intimated of the same.

       (3) Papers presented at the National Con
    ference may be reproduced in full or part thereof
    in any other Journal after obtaining permission
    from the Secretary-General of the Association and
    the acknowledgement to be read as : “This paper
    was presented at the .. . National Conference on
    TB and Chest Diseases held at. . . and has been/is
    being published in the Proceedings of the

           Indian Journal of Tuberculosis
Vol. XVI                       New Delhi, April 1969                          No. 2

        An unusual observation and deductions therefrom for possible cause
of such an observation is, generally, the mother of research. A real research
worker will not rest content with this only. He will, thereafter, take suitable
steps to solve problems arising out of such an observation. This is how man
has delved into the depths of the unknown and collected figures and facts for
the benefit of mankind.

         Many epoch-making discoveries were made in the past by individuals.
Because of rapid advances in medical and sister sciences, and development of
specialities, individual effort is being replaced by that of a “team” in solving
most of the problems. It has, however, to be conceded that the fountain of
research is still the individual with a bent of mind for careful observation
and deductions therefrom. To get the right answer or, in other words, to
fulfil the objective of the study, the planning, conduct and evaluation of the
findings should be entrusted to a suitable ‘team’ of experts.
         Most often, specially for operational research, inclusion of a “Statis-
tician” is of vital importance in a research team.
        It is obvious that such a “team” must work like a well-oiled machine.
For this purpose, all members of the team must clearly understand each
other’s views and stand-points. The problem to be investigated must be
defined, expressed in an unambiguous language and should, preferably, remain
clear of other issues. Terminologies to be used for accord must also be
defined in clear and simple language. Planning of the study should take into
account all possible sources of errors and biases with an effort to eliminate
or diminish them. Many other factors may also have to be considered. The
design of a study must, therefore, be built with great care in which every
participant should have his say and share of responsibilities. All these spokes
in the wheel of study must be in the realm of practicability, and should
strengthen confidence in the final interpretations and conclusions.
        The practice of seeking help of a “Statistician” at a late stage for
interpretation of data and drawing conclusions is utterly wrong. The data
                                                       Ind, J. Tub., Vol. XVI, No. 2

can be correctly interpreted only when the design of a study is adequate
and information rightly recorded. Besides, and this is most important, the
data must be interpreted with common sense in relation to the purpose and
picture of the structure of the study. The Statistician must, therefore, be
associated from the start to the finish of a study. He should be deeply invol-
ved in planning, check its conduct, agree to any interim modification of the
plan necessitated by unforeseen conditions and finally have the largest say in
the evaluation. This is true both for a planned and retrospective study.

      India is largely involved in the field of operational research to develop
a suitable tuberculosis control programme. Few well-equipped institutions
may have the resources to plan such studies. This is hardly possible for
others. At the same time, the subject of tuberculosis is such that data, res-
tricted by uneven distribution of regions, may have many failings. To obviate
this, well-planned and supervised co-operative studies, designed by a team of
experts, appears to be the best method. It increases immensely the confidence
not only in the conclusions but also their acceptability for the country’s cont-
rol programme.

          Writing a paper on a study is also an art. The manner of presenta-
tion should differ in long and short publications and at Conferences. For the
latter, tables etc. to be projected should not usually contain details but should
be clean and highlight the important points only. In short, the presentation
should take into account the consumers and allotted space or time.

     The four papers on Statistics published in this issue of the Journal
provide valuable guide-line in regard to utilisation of statistical methods in
medical research.

 Ind. J. Tub., Vol. XVI, No. 2
                        AWARD OF T.A.I. GOLD MEDAL
      The Fourth Award of the Tuberculosis Association of India’s Gold
Medal for outstanding work in the Tuberculosis field was conferred on
Dr. P. V. Benjamin at the time of the 24th National Conference on Tuber-
culosis and Chest Diseases held in Trivandrum in January 1969.
                                                 tion of BCG Vaccination in India. He persua-
                                                 ded the various Universities to institute
                                                 Diploma Courses in Tuberculosis Diseases.
                                                 He set up a separate Section for Tuberculosis
                                                 in the Directorate General of Health Services.
                                                 He advocated domicilliary treatment of
                                                 patients and prepared suitable schemes for the
                                                 purpose in the national development pro-
                                                 gramme. He was responsible for the esta-
                                                 blishment of the National Tuberculosis
                                                 Institute in Bangalore, the Chemotherapy
                                                 Centre in Madras, the Tuberculosis Research
                                                 Centre at Madanapalle and for starting TB
                                                 Training and Demonstration Centres in
                                                 different States. He initiated the National
                                                 Sample Survey in 1956-57 and a number of
             Dr. P. V. Benjamin                  research programmes.

    Born on 21st January, 1896, Dr. P.V.             Dr. Benjamin conducted in 1943 a Survey
Benjamin graduated from Madras Medical           of sanatoria in India with a view to provide
College in Medicine in 1922. After taking his    accommodation for TB patients in the Indian
Diploma in Tuberculosis Diseases at Cardiff      Army. As a member of the TB Sub-Committee
in 1930-31 he toured extensively the Scandi-     of the Health Survey and Development Com-
navian countries, Europe, Germany, the U.K.      mittee he submitted the Memorandum on
and the U.S.A. to study the anti-tuberculosis    tuberculosis. He was a member of the Health
work in those countries. He was                  Panel of the Planning Commission. He was
attached to the Union Mission TB Sana-           closely associated with the Indian Council of
torium from 1922 as one of its senior doctors    Medical Research. He contributed a Section
and was its Medical Superintendent for over      on “Tuberculosis in the Tropics” in the book
ten years. He became Medical Commissioner        “Symposium on Tuberculosis” written by Prof.
of the Association in 1941 and in 1944 was       Heaf of Cardiff.
designated as its Technical Adviser. In 1948
he was appointed as TB Adviser to the Gov-           Dr. Benjamin is well-known among the
ernment of India and continued functioning as    international group of TB workers. He was a
Technical Adviser to the Association. He         delegate to the first Empire TB Conference
retired from Government service in October,      held in London in 1937 where he presented a
1962 but continued as Technical Adviser to the   paper on ‘Indian People and the TB Problem’.
Association upto the 1st of July, 1964.          He attended almost all International Confer-
                                                 ences in TB subsequently. He was closely
   Dr. Benjamin is an ardent champion of         associated with the International Union and
voluntary work and did his best to promote       was a member of its Executive Body, Council
the work of the TB Association. He was           and Technical and Programmes Committees
member of the Technical Committee of the         for several years. He was President of the
Association from its inception in 1948 upto      International Union during 1955-57 and
1964 and was President of the Nineth Tuber-      presided over the XIVth International TB
culosis Workers’ Conference held in Lucknow      Conference held in New Delhi in January,
in 1952. He was Editor of the Indian Journal     1957. He visited several countries in the East
of Tuberculosis from 1953 to 1964. He was        in connection with the formation of the
responsible for introducing the TB Seals Sale    Eastern Regional Committee of the Interna-
Campaign in India, for developing the Mehrauli   tional Union and was its President from 1957
TB Hospital and for upgrading the New Delhi      to 1964. He was a member of the W.H.O.
TB Clinic as a Training and Demonstration        Expert Committee on Tuberculosis for a
Centre. He was responsible for the introduc-     number of years and was consultant to the
                                                           Ind. J. Tub., Vol. XVI, No. 2

W.H.O. Seminar on Tuberculosis held in               Dr. Benjamin is regarded as the ‘Father’
Sydney in May, 1960. He represented India at     of the anti-tuberculosis movement in India and
the South East Asia Regional meeting of the      as an ‘Elder Statesman’ among international
W.H.O. held in Djakarta, Indonesia, in 1955.     experts. He was awarded the Kaiser-I-Hind
He advised the Nepal Government in regard        Gold Medal in 1945. He was awarded in 1955
to their anti-tuberculosis work. He has pub-     TADMA SHRF by the President of India
lished over 100 papers on survey, research and   and the Sir Robert Philip Gold Medal by the
various aspects of tuberculosis. He was made     N.A.P.T., London. In recognition of his
Honorary Life Member of the International        outstanding services the Tuberculosis Associa-
Union Against Tuberculosis at its meeting in     tion of India is honouring him with its Gold
Amsterdam in 1967.                               Medal-1969.

 Ind. J. Tub., Vol. XVI, No. 2
                           PLANNING OF RESEARCH STUDIES*
                               (Some General Considerations)
                                          S. S. NAIR
                        (From National Tuberculosis Institute, Bangalore)
Need for a perspective on research                  be necessary to find a speedy solution to this
                                                    basic problem.
    Research is a word which is commonly
used now in many walks of life. But it is           What is research ?
doubtful whether it has a commonly accepted
meaning among medical research workers or               Research has been defined by Bernard Ostle
even among the smaller group of tuberculosis        as an inquiry into the nature of, the reasons
and chest diseases workers. Some have their         for, and the consequences of any particular set
own pet idea of research and are indifferent        of circumstances—whether these circumstances
to or even cynical about other forms of re-         are experimentally controlled or recorded just
search. It is important to accept a general         as they occur. To be of value, research must
definition of research and to recognise that all    provide reproducible results which can be
types of research are valuable and also that        extended to more complicated and general situ-
their relative importance may change from           ations, at least to a limited extent. Research
time to time. The progress of research can be       has also to be considered as a continuous pro-
substantial and real only if research activities    cess involving the following stages:
are guided with a proper perspective of such
changes in the relative importance of the vari-        1.   Careful study of available data to for
ous types of research. A disproportionate em-               mulate hypotheses to be tested in a new
phasis on certain out-moded forms of research               study,
can prove to be very detrimental to speedy
scientific developments. This dynamic appro-           2.   Designing a proper experiment or
ach necessarily implies that a small group of               study to test these new hypotheses,
experienced research workers, with proper              3.   Collection of data by careful experi-
perspective of the trends and future needs of               mentation or observation,
research should provide the necessary guidance
and co-ordination to a band of research wor-           4.   Testing the new hypotheses on the
kers with appropriate attitude towards                      basis of the data collected, and
research.                                              5.   Careful study of observations which are
                                                            not in agreement with accepted hypo
Attitude towards research                                   theses and formulation of other hypo
     The importance of a proper attitude towards            theses, if necessary.
research has been emphasised by many eminent
scientists. In 1949, Sir George Pickering,              Any research study could be expected to
Regius Professor of Medicine in the University      serve a dual purpose. Firstly, it provides data
of Oxford stated that the attitude of mind          to test the hypotheses or answer the questions
“tends to be ominicient rather than admit           which prompted the study. Secondly, a care-
ignorance, to encourage speculation not solidly     ful study of the data could result in the formu-
backed by evidence, and to be indifferent to        lation of new hypotheses to test which further
the proof or disproof of hypotheses. And, it        studies are required. If the first purpose is not
is above all, to this habit of mind so inimical     served it is bad planning and if the second is
to scientific inquiry that the experimental         not done it is a failure to take advantage of all
method has found so small a place in clinical       the information which has been collected.
studies”. It will be quite instructive for each     Sometimes, research workers are tempted to
one of us to ponder and judge for ourselves         reject or ignore those observations which do
whether this statement, made 20 years back,         not fit in with their hypotheses. This practice
still holds good, and if so to what extent. Can     is not desirable. In fact, these unexpected obser-
we at least have the satisfaction that it is no     vations are likely to provide golden opportuni-
longer true for the majority of medical research    ties for the research worker to get closer to the
workers in India. If not, there is room for         truth. Let us remember that it is the isolated
considerable improvement in this respect and        light-house and not the cluster of houses that
concerted efforts over the whole country may        help the sailors to reach their destination. The
  * Paper read at the 24th National Conference on   need for and importance of an objective scru-
    TB of Chest Diseases held on Trivandrum in      tiny of unexpected observations is often not
    January 1969.                                   clearly understood.

                                                                   Ind. J. Tub., Vol. XVI, No. 2
38                                                S. S. NAIR

    It is also instructive to remember that there                   (e.g., normal blood pressure, blood
are two clear trends in research, which are                         sugar level etc.)
somewhat contradictory. While there is a ten-
dency for extreme specialization on the part of                5.   studies to develop diagnostic techniques
individual research workers, most research                          by measurement of sensitivity, specifi-
problems are such that many disciplines and                         city and overall accuracy, and
fields of specialization have to collaborate for
finding the best solutions to the problem. These               6.   operations research to achieve maximum
two trends imply that the individual research                       efficiency in the application of existing
worker has to understand and maintain a proper                      knowledge and skill.
balance between specialized research and
collaboration in research on multidisci-                     The first type has been and shall always be
plinary team basis. Thus, we should not (and             of fundamental importance. Based on the
probably could not) any longer refrain from              foundations so provided, types 2 to 5 evolve
identifying ourselves as an army of research             the technical knowledge necessary to achieve
workers, who have to collaborate sooner                  the cure and control of diseases. Type 6
or later so that quicker progress can be obtain-         deals with all aspects of conducting or opera-
ed in both quality and quantity of research              ting a system in its natural environment and
work. Such an army of research workers                   recognises the fact that technical knowledge is
should have a proper understanding of the                only one of the components of the system. In
planning of research studies and should be               these days, when the efficient management
amenable to a self-imposed research discipline           of any organisation or programme, be it big
which alone can ensure research work of                  or small, depends not only on the level of
uniformly good quality.                                  technical know-how but also more and more
                                                         on many operational factors, the importance
Types of studies                                         of operations research is being increasingly
                                                         recognised in many fields. It is only a matter
    Research studies could be broadly classified         of time that these concepts will find easy
in a number of ways. One type of classification          acceptance among medical research workers
is into prospective and retrospective studies.           also. The earlier this trend is visualised and
The latter cannot generally provide such clear           acted upon, the more advanced and substan-
cut and reliable answers as the former, and              tial can be our contribution to the speedier
might even be misleading if not cautiously               development of medicine and public health.
used. Yet, these have an important place. For
example, double events such as congenital de-                A third manner of grouping research
fects following an attack of some diseases can           studies is on the basis of whether the results
be studied only when these occur by chance               obtained directly contribute to a practical
from time to time and cannot be planned.                 course of action or mainly contribute to
Similarly, we cannot submit mankind to a                 knowledge only. Whatever the method of
large scale smoking experiment for 20 to 30              grouping, it is important to remember that
years to measure the relative frequencies of can-        many types of research studies are possible
cer of the lung among smokers and non-smo-               and that the type of study to be chosen will de-
kers. Retrospective studies provide valuable in-         pend on the objectives of the study.
formation in such instances. This category of
studies can also be used to formulate hypothe-           Defining the Objectives
ses for further prospective studies.                         A clear formulation of the objectives is the
                                                         first step in planning of research studies. This
    Research studies could also be grouped               is also the most crucial step because every
according to the fields or aspects they cover            subsequent step in the study is dependent on
viz.,                                                    the objectives. For instance, the composition
                                                         of the study groups and the accuracy required
     1.   basic research,                                for the measurements or observations are
                                                         dependent on the objectives of the study.
     2.   controlled trials (e.g., for testing effica-   Sometimes slight variations in the objectives
          cy of drugs or vaccines),                      may have to be accompanied by vast changes
                                                         in the design of the study and may even re-
     3.   epidemiological and sociological sur-          quire the choice of another type of study al-
          veys,                                          together. For instance, a comparison of the.
                                                         allergy inducing capacity of two BCG vaccines
     4.   studies to define ‘normals’ to judge           can best be studied by a simple controlled
          point or level for ‘some abnormality           trial with a trained team of field workers. Let
 Ind. J, Tub., Vol. XVI, No. 2
                                  PLANNING OF RESEARCH STUDIES                                     39

the objective be changed to camparison of            of the study and the size of the study popula-
allergy inducing capacity of two BCG vaccines        tion to be examined or observed. It is also
under field conditions. With the addition of         important to expLaln to the statistician all the
the last three words to the objective, a number      aspects which are relevant or may be even
of complicating factors such as effect of varia-     doubtfully relevant to the problem and the
tions between teams of technicians, differen-        onus for this must rest with the research
tial effect of storage on the two vaccines etc.,     worker.
crop up. The problem can then be studied
only with the help of a considerably more com-       Type of Study to be chosen
plicated design and may even require a series
of studies.                                              Once the objectives of the study are clearly
    In defining the objective it is essential that   formulated the choice of the best type of study
the exact sense in which each term is used is        becomes fairly obvious. However, practical
known and thoroughly understood. It is also          considerations may restrict this choice. For
necessary that the objectives are stated as com-     instance, if making fresh observations in a
pletely as possible and do not leave room for        planned manner is not practicable, only re-
different interpretations regarding the context      trospective studies could be attempted even if
and scope for generalisation. If the study is to     a prospective study is considered to be more
form the basis for a practical course of action,     suitable. Similarly, limitations of resources
the expectations in this respect should also be      may also limit the choice to the second best
clearly stated.                                      type of study. These restrictions might also
     It would be a good working principle to         involve a re-formulation of the objectives.
formulate in advance, on the basis of available
knowledge, as many hypotheses which can be           Design of the Study and Allocation
studied with the available resources. Such an        into Study Groups
open-minded approach is the essence of good
planning and prevents a dogmatic attitude.               The design of a study is the complete se-
To quote Francis Bacon “If a man will begin          quence of steps considered in advance to en-
with certainties he shall end in doubts, but if      sure that the appropriate data will be collected
he will be content to begin with doubts he           in a systematic and well defined manner so
shall end in certainties”. During the prelimi-       that an objective analysis of these data could
nary stage of formulating one’s doubts or            lead to valid inferences about the problem
hypotheses it is important to ask oneself ‘can       under study. Design of the study should be
this hypothesis be tested by an experiment and       the primary responsibility of the statistician.
if so in what manner ?’ This will help a great
deal in selecting out the hypotheses to be tested       The requirements of a good design are that:
by the proposed study and thereby lead to a
clear enunciation of the objectives of the pro-         1. The comparisons to be made should
posed study.                                               be, as far as possible, free from syste
                                                           matic error, bias and influence of the
Scope of the Study                                         factors which cannot be separated, eg.,
                                                           if initial and follow-up X-ray pictures
    Closely related to the objectives of the               are read by different readers, the
study is its scope. While the objectives define            change in status cannot be ascertained
what we want to find out about a particular                correctly because reader differences
population, the scope is the extent to which the           also play a part and cannot be separa-
findings from this population can be generali-             ted. Similarly any systematic error
sed. For instance, the findings from a repre-              or bias affecting one group will also
sentative sample of patients attending an urban            be merged with other differences bet-
clinic can be strictly true only for patients              ween this group and the other groups
attending that clinic, but can be generalised to           studied.
patients at other similar urban clinics in that
city or town and may be to such patients in other       2. The comparisons should be made suffi-
urban areas also. The extent to which such                 ciently precisely and it must be possi-
generalisation can be made depends upon how                ble to assess the uncertainty or lack of
far the particular population studied is repre-            precision in the conclusions. To en-
sentative of the population for which the                  sure this, it is necessary to, allocate the
Results have to be generalised. Both objectives            study population into different groups
and scope of the study should be thoroughly                on the basis of the statistical principles
discussed with the . statistician so that he could         of random sampling and estimation
assist in selecting the type of study, the design          of error.
                                                                     Ind. J. Tub.,. Vol. XVl, No. 2
40                                           S. S. NAIR

     3.   the conclusions should have as wide a     and the data collected will therefore be based
          range of validity as possible without     on differing definitions. This is particularly
          decreasing their precision,               true when observations are recorded in a
                                                    number of centres or over a long period of
     4.   the experimental arrangement should       time.
          be as simple as possible, and
                                                    Conduct of the Study
     5.   there should be a reasonable balance
          between precision of the conclusions          During the course of the study, adequate
          and the cost of the study. If the         supervision should be exercised to ensure that
          conclusions are not reasonably precise    the work instructions are followed strictly.
          the study is almost useless, but aiming   This has to be visualised at the planning stage
          at an unnecessarily high degree of        itself and arrangements should be made to
          precision implies avoidable wastage.      ensure regular flow of information to a statisti-
          This is so, because, other conditions     cal unit which can thoroughly scrutinise the
          remaining the same, the precision of      data collected and report on departures from
          the comparisons between any two study     work instructions. This is particularly import-
          groups increases or decreases as the      ant in the early stages of the work and could
          number of persons studied in these        prove very useful to the supervisor. This
          groups increases or decreases.            process of scrutiny of records and supervision
                                                    should be continued throughout the study so
    In studies dealing with uncontrolled popula-    that uniformly good quality of data can be
tions, it is essential that very high coverage of   collected. Choosing the best type of study and
the study population should be obtained. If         a proper design and absolute accuracy in
this is not possible the design should include      analysis and interpretation of data will be of
collection of other relevant information regard-    no use at all if the basic data are incorrect or
ing the non-respondents to find out whether         unreliable in any way. It is not unusual to
they form a special group.                          find that data are collected in a hotch-potch
                                                    manner under the wrong impression that
    At the time of finalising the design of the     analysis can get something useful out of it,
study, it would be helpful if the outline of the    especially if a statistician can juggle with it.
type of tables (i.e., dummy tables) for analysis    Adequate Provision for Analysis and
of data and the statistical tests of significance   Interpretation
for proper interpretation of the data can be
visualised. This helps in ensuring, before it is        At the time of planning a study, adequate
too late, that the study population and its         provision should be made for analysis and
allocation according to the design are suitable.    interpretation’ of data. This is particularly
Also, wastage, by collection of unnecessary         important for larger studies. This aspect is
details which will not be made use of later, can    often ignored till the study is completed and
be avoided.                                         leads to considerable delay in preparation of
                                                    the report. Even more important is the
Preparatory Work                                    continuity of the staff from planning to report-
    The next important step is the preparation      ing. The team of research workers (including
of forms and cards for recording of informa-        the statistician) who have planned the study
tion during the field or laboratory work and        and lived with it will know the pros and cons
of detailed work instructions to each category      of the material very intimately and they alone
of staff concerned, on how to carry out each        can do full justice to it at the reporting stage.
step of their work and record their observations.
These cards and forms as well as the work           Need for Collaboration with the Statistician
instructions should be pre-tested during a pilot
phase and finalised on the basis of this experi-        The foregoing paragraphs have also indicat-
ence. If necessary, further training should be      ed the need for a close collaboration between
given to the staff before starting the actual       the medical research worker and the statistician.
study. It is important to ensure that the           It would be instructive to consider the current
definitions and terms used are thoroughly           practices in this respect. A perusal of the
understood and uniformly interpreted by each        current literature shows that there is an
member of the staff concerned. Definitions          increasing “prevalence” of the statistical
can often be misinterpreted during actual           methods in scientific studies. But, unfortunately,
observations and recording of data. Each            to some extent at least, this is based, not on an
interpretation is in effect a separate definition   understanding of the underlying reasons but on

 Ind. J. Tub., Vol. XVI, No. 2
                                 PLANNING OF RESEARCH STUDIES                                    41

the assumption that use of tables, graphs and operative studies become all the more import-
mathematical formulae give more authenticity ant. Important findings from a study in one
and respectability. It is not uncommon to find part of the country could be generalised with
reports on some truly subjective studies which more confidence, if similar studies are conduct-
have thus been invested with a false show of ed under different realistic conditions. Such co-
objectivity. The lack of proper appreciation operative studies become all the more
of the importance of statistical thinking and important in operations research because the
methods at various stages of a research study practical conditions under which knowledge
has similarly led to varying levels of collabora- and skill are actually applied for the benefit of
tion with the statisticians. Sometimes such the community or nation introduce a number
collaboration is considered as a formality to of key variables which have great influence on
ensure financial resources or to bestow a stamp the outcome. Some factors considered to be
of acceptability. There are also instances of technically important pale into insignificance
collaboration which are on a par with the in the light of some of these key variables.
following answer to the question, “Do you
believe in ghosts ?” “No, but I am afraid of Need for a Rigid Research Discipline
them”. The belief that statisticians deliberately
make simple questions difficult is also not            The success of such co-operative studies
uncommon and could have retarded the growth         would depend upon the participating units
of healthy collaboration between the doctors following a rigid research discipline. Even
and statisticians. Successful collaboration studies in one area only, will become more valu-
demands that the statistician should learn all able if the quality of the research work becomes
he can of the problem in question and the uniformly good and reliable. What is often
medical man should learn all he can about the not recognised is that a self-imposed research
statistical approach. Without substantial discipline is essential among research workers.
knowledge on both sides it might turn out to The more rigid it is, more valid will be the
be, blind leading the blind. Those research conclusions and more comparable will be the
workers who are reluctant to learn or apply the findings of different studies. Whereas problems
statistical approach may not have realised that vary from area to area and population to
a new language is a riddle before it is conquered population, the research discipline need not
but a power in the hand afterwards. In any vary, as the basic concepts are fundamental
case, it is important to remember that the time and uniformly applicable. The reasons for the
for consulting a statistician is before planning lack of self-imposed research discipline can,
the study, during the planning, during interim therefore, be only artificial or man-made.
review to ensure good quality of data and
during the analysis and interpretation—in fact, Conclusion
he should be involved in all stages of the study       Some of the statistical principles which have
whenever possible.                                 to be kept in mind while planning research
                                                   studies and the various steps that have to be
Need for Co-operative Studies                      gone through have been indicated earlier. It
                                                   would be a very revealing experience to go
    The field of medical observation is compli- through the research studies already under-
cated because of some inherent variations. No taken or in progress and see how many of these
one doctor can treat sufficient number of cases satisfy these principles or have gone through
in a short span of time and a large number of the various steps listed. It is not unusual to
doctors may each treat a few cases. The cases find reports of research studies in which the
themselves are far from being a homogeneous questions or objectives are either not clearly
group. The research worker in the field of formulated or are not stated at all. Sometimes,
public health faces the further difficulty that he the type of studies chosen, the design, the study
cannot set up and control his own experiment population and the analysis are not suited to
in his own laboratory or clinic. In such provide valid answers to the questions formu-
circumstances, both for clinical and public lated or the hypotheses to be tested. Lack of
health research co-ordinated team work in the adequate arrangements for continuous super-
same area or spread over a number of areas vision and scrutiny of methods of observation
is often necessary. In the absence of such co- and recording is much more common than
operative studies the literature becomes full of normally visualised. There are also instances
cLalms, assertions and counter assertions each which remind one of the saying that “statistics
of them being correct in its own limited are used the way a drunkard uses a lamp post;
manner, like the four blind men describing the for support rather than for light”. The only
elephant. In a country like India, where practicable remedy for these situations is a self-
conditions can vary to a large extent such co- imposed research discipline.
                                                             Ind. J. Tub,, Vol. XVI, No. 2

                                           S. RADHAKRISHNA
                           (From Tuberculosis Chemotherapy Centre, Madras)

    The controlled clinical trial is now a well-           very clearly the type of patients to be admitted.
accepted method of measuring the relative effi-            To give an example, Slide 2 sets out the impor-
cacies of different therapeutic regimens for               tant criteria employed at the Tuberculosis
many diseases. Although its usefulness is                  Chemotherapy Centre, Madras.
widely appreciated, there is an insufficient
awareness of the rationale and the methodology                 2. Choice of Patients for study at the T,C.C.,
of the controlled clinical trial—that is, the rea-                               Madras
sons underlying it and the procedures involved
in the execution. By taking examples from the
field of pulmonary tuberculosis, the isssues in-              1. Aged 12 years or more
volved can be clearly set out.                                2. No previous chemotherapy
Specification of regimen and priority in aims                 3. Bacteriologically confirmed pul. Tb.
    To evaluate the efficacy, toxicity and accep-             4. Drug-sensitive organisms
tability of an anti-tuberculosis regimen—for                  5. Bonafide residents
instance, isoniazid plus thioacetazone, it is
necessary to start with very clear ideas of the
dosage, the rhythm of administration and the                   It is important also to specify centra-indica-
exact duration of the regimen. Next comes                  tions for admission to the study—for example,
specification of the order of priority in aims as          patients with leprosy or diabetes, since their
there can be a clash of interests. For instance,           management would be rather complicated.
   I. Specification of Regimen and Priority in Aims
                                                               The next requirement is a control group of
 Specify clearly
                                                           Need for control
        (a) dosage, rhythm and duration
        (b) priority in aims                                   Slide 3 gives some interesting examples
                                                           of entirely inaccurate or highly misleading con-
             (1) Efficacy                                  clusions that one might draw in the absence of
             (2) Toxicity                                  a control group of patients.
             (3) Acceptability
                                                                           3. Need for Control

if the main aim is to determine the efficacy of
the drugs, it will obviously be necessary to
employ procedures for detecting irregularities                                   Rx for 3 years      I%of77
                                                           Relapse rate
in drug-collection and drug-intake, and correct-                                 Rx for 2 years      0% of 74
ing them. Such action would, however, mean
that pressure is applied on patients when they
show evidence of non-acceptability, thereby                                      Strep. + 1NAH          35% of 78
making any assessment of the acceptability of              Giddiness
the regimen rather artificial. This is a good                                    PAS + 1NAH          11% of 70
illustration of the basic maxim that any study
can have only one main aim.                                   The first example refers to relapse rates in
Choice of patients for study at the T.C.C.,               patients with bacteriologically quiescent tuber-
Madras                                                    culosis. In patients who received chemotherapy for
                                                          3 years, the total relapse rate in the third, fourth
    For any generalisation to be possible from            and fifth years was only 1%. This low proportion
the results of a study, it is necessary to define         could have led to the recommendation that 3 years
                                                          of chemotherapy is absolutely necessary to keep
    * This paper was presented as a lecture at the 24th   the relapse rate low. (Indeed, similar
National Conference on TB and Chest Diseases, held        recommendations have been made in the
in Trivandrum in Jan. 1969                                literature, in the absence of controls). Such
 Ind. J. Tub, Vol. XVI, No. 2

a recommendation is, however, totally unwarn-      standards for smears, cultures, sensitivity tests
ted since, in the patients who received only 2     and urine tests. Obviously, the only way out of
years of chemotheray, the relapse rate was         these dangers is to have a control group that
0%.                                                is concurrent.
    The next example is a less extreme one, and
pertains to toxicity. In a group of patients       Number of patients to be admitted
treated with a twice-weekly regimen of strep-
tomycin plus isoniazid, 35% compLalned of              Next, let us consider the question which is
giddiness on at least one occasion during the      most frequently posed to the statistician, namely,
year of chemotherapy. However, 11 % of the         “How many patients must I admit to the study
control group (who received a standard regi-       to obtain a statistically valid result ?” Unfor-
men of PAS plus isoniazid) also compLalned of      tunately, the short answer to this question is
giddiness. Thus, in the absence of the control     that there is no such magic number. However,
group, we would have acquired an exaggerated       if the clinician can indicate to the statistician
picture of streptomycin toxicity.                  the approximate efficacy of the control regimen
                                                   and, furthermore, state what difference from
    Examples like this are plentiful. For ins-     the control regimen he would regard as having
tance, in the treatment of tuberculosis, conclu-   practical importance, the statistician can then
sions about the value of gold therapy, value of    tell them approximately how many patients
hospitalization and role of diet have been         should be admitted.
drawn and, in the case of the latter two, are
still being drawn without having a control             To take an example, the clinician might be
group of patients.                                 interested in the new regimen only if it is 20%
    These examples will have convinced you of      more effective than the control regimen, which
the necessity for having a control group of        from previous experience is known to have an
patients. In the present context, the control      efficacy of 75%. In this case—that is, an effi-
might be a regimen that is already in use at       cacy of 75% for the control and 95% for the
your clinic, for instance, a standard regimen of   new regimen, approximately 70 patients will
isoniazid plus PAS.                                have to be admitted to the study (that is, 35 in
                                                   each series) to demonstrate statistical signifi-
Need for concurrency                               cance. If, however, the clinician wishes to
               4. Need for Concurrency                    5. Number of Patients to be Admitted
 Factors that could vary                                 Control           New              No. of patients
                                                         regimen           regimen          to be admitted
   1. Disease condition of patients
                                                          75%                 95%                 70
   2. Co-operation of patients
   3. Clinic supervision                                  75%                 90%                 130

   4. Laboratory standards                                75%                 85%                 290
                                                          75%                 80%                 1150

      Next, it is essential that the control
should be a concurrent one. Comparisons with
a non-concurrent control—that is, retrospective    detect a smaller degree of superiority, say 15%
comparisons—are usually dangerous, as there        (that is, an efficacy of 90% for the new regi-
are many factors that could vary from one point    men), the number required will be 130. The
in time to another. For instance, the disease      corresponding number for a 10% superiority
condition of the patients admitted to              will be 290, and fora 5% superiority 1150.
treatment might be different in different years,   Thus, the smaller the difference to be detected,
on account of changes in diagnostic measures       the larger will be the number of patients
or influence of mass propaganda campaigns.         r e q u i r e d . I t mu s t b e n o t e d t h a t t h e
The co-operation displayed by the patients         number required for statistical significance will
might also vary from one year to another,          depend not only on the size of the difference
possibly due to socio-economic causes. Thirdly,    to be detected, but also on the absolute levels
the intensity of examination and the overall       of efficacy of the two regimens.
quality of the clinic supervision might be
different, especially if there have been changes
in the personnel. A similar problem can arise          It is worth stressing at this stage that statis-
with the laboratory                                tical significance need not be the sole criterion

                                                                    Ind. J. Tub., Vol. XVI, No. 2
44                                           S. RADHAKRISHNA

for determining the number of patients to be           rapy in myocardial infarction (quoted by
admitted. Very often, we are just as interested        Truelove), the system of alternation resulted
in obtaining as precise an estimate as possible        in 580 treated patients and only 442 control
of the efficacy of the new regimen. Obviously,         patients, a difference that could have occurred
the larger the number of patients admitted, the        by chance in only 1 of 5,000 occasions.
more precise will be the estimate. For instance,           The best protection against all accusations
if the efficacy was found to be 80% in a sample        of bias is random allocation from sealed
of 100 patients, it may be stated, with 95%            envelopes. This procedure may be regarded as
confidence, that the true efficacy lies within         the equivalent of tossing a coin. In practice, it
80±8%. ‘If, however, the efficacy of 80% had           consists of preparing a treatment regimen list
been observed in a larger sample of patients,          for successive patients based on random num-
say 400, the limits will naturally be narrower,        bers that are available in statistical tables and
namely, 80±4%.                                         incorporating it into sealed envelopes. Each
     Summing up, the decision regarding the            sealed envelope must have written on its exte-
 number to be admitted must be based on objec-         rior the name of the study, and a sequential
 tive considerations like statistical significance     serial number. Inside each envelope, there
 and high precision. Practical considerations          should be a slip of paper giving the name of
 like availability of patients, drugs and facilities   the study, the sequential serial number and the
 are no doubt important but should always be           regimen for the patient. When a patient is
 regarded as secondary.                                found suitable for admission to the study, his
                                                       treatment regimen is to be determined by
Mode of deciding the regimen for individual            tearing open the next in the series of sealed
patients                                               envelopes.
    Next comes the mode of deciding the treat-         Purpose of random allocation
ment regimen for individual patients. In a
controlled clinical trial, the mode of deciding            The purpose of random allocation is to
the regimen for any individual patient must            avoid personal preferences in the choice of
not only be free of bias, but also appear to be        treatment for individual patients. It has to be
free of bias. One can readily see the danger in        emphasised that these personal preferences can
entrusting the choice of the regimen for indi-         be conscious or, more often, sub-conscious.
vidual patients to the clinician. To take a simple
                                                                  7. Purpose of random allocation
     6. Mode of deciding the Regimen for individual
                                                         1. To avoid personal preferences,
     1. Clinician’s choice                                  conscious or sub-conscious
     2. Alternation                                     2 To construct two groups similar in all aspects
     3. Random allocation from sealed envelopes              (a) known and measurable (stratification)
                                                             (b) known but immeasurable
 example, if patients were to be treated at home             (c) unknown
 or in sanatorium at the clinician’s discretion
 (which might be, in some instances, influenced
 by the patient’s wishes), it is almost certain that   Failure to recognise that there is such a thing
 the iller patients would tend to be admitted to       as sub-conscious bias has often led investigators
 sanatorium while the less ill patients would be       to regard random allocation as a slur on their
 treated at home.                                      personal honesty.
     Another highly undesirable procedure is the           The great advantage of random allocation
 method of alternation, whereby the first patient      is that it is highly likely to result in the cons-
 is prescribed regimen A, the second regimen B,        truction of 2 groups which are similar in all
 the third regimen A, the fourth regimen B, and        aspects—known and measurable, known but im-
 so on. A variant of this is to admit all pati-        measurable or not measured, as well as the un-
 ents on odd days to the regimen A and those           known. In the case of known and measurable
 on even days to the regimen B. Such proce-            characteristics that have prognostic importance,
 dures are, however, capable of bias because the       a further precaution would be to stratify the
 order in which patients are admitted to a study       patients into 2 or more groups—e.g. non-cavita
 can be manipulated without much difficulty.           ted and cavitated—and undertake the allocation
 For instance, in a study of anticoagulant the-        from separate series of sealed envelopes, one for
  Ind. J. Tub., Vol. XVI, No. 2
             PLANNING, CONDUCT AND EVALUATION OF CONTROLLED CLINICAL TRIALS                                  45

each group. In the present example, this                detail—that is to say, no deviations can be
procedure will ensure that the two series have          made to suit the needs of individual patients or
identical proportions of cavitated patients.            individual clinicians.
                                                             To facilitate strict adherance to the protocol,
Similarity in subsequent management                     it is useful to have the important aspects (e.g.
                                                        criteria for eligibility to study, intensity of the
    Next, it is important to ensure similarity in       x-ray and sputum examinations, weight-dosage
the subsequent management of the patients in            schedules) abstracted on to separate sheets of
the 2 series. For this, it is necessary to set out      paper that are readily available to the clinicians
in advance (1) the intensity of examination             and nurses ; also, diaries for reminding clinic
during treatment—clinical, x-ray, sputum etc.,          staff of ensuing examinations should be kept.
(2) the nature and frequency of checks on drug-         These are what can be termed as reminder
      8. Similarity in subsequent management            systems. Despite these, deficiencies can occur ;
                                                        it is therefore necessary to have systems for
   1. Intensity of exam.—clinical, x-ray, sputum etc.
                                                        detecting deficiencies and rectifying them before
                                                        it is too late.
   2. Checks on drug-regularity                              Well-designed forms and analysis cards
                                                        make analyses easy ; therefore much time
   3. Defaulter action                                  must be spent on them at the design stage.
   4. Observance of toxic symptoms                      Also, information collected should be abstrac-
                                                        ted periodically on to analysis cards. This
   5. Criteria for withdrawal from study                will not only facilitate interim analysis, but also
                                                        highlight deficiencies in the forms, cards and
                                                        recording systems, which can then be rectified.
regularity, (3) procedures for dealing with                  As bias can creep in to laboratory investi-
defaulters, and (4) procedures for the recording        gations, it is important to devise systems in
of symptoms of toxicity. Finally, and most              which there is not even scope for bias. For
important, the circumstances under which a              instance, when smears are examined, or cultu-
patient may be withdrawn from the study must            res or sensitivity tests read, or urine tests under-
be stated very clearly. For instance, the criteria      taken, it should be arranged that the laboratory
could be serious radiographic or clinical dete-         technicians are unaware of the source of indi-
rioration in the presence of a positive sputum of       vidual specimens.
major drug-toxicity. It must be emphasised that              Finally, it is essential to have quality con-
all these procedures must be implemented alike          trol for laboratory tests and for drugs that are
for all patients, regardless of the treatment           in use in the study. At the Tuberculosis Chemo-
regimen.                                                therapy Centre, we keep track of the standards
Conduct of the study                                    in the laboratory investigations by slipping
                                                        in controls without prior warning and by perio-
    All that has been said so far relates to the        dic reviews of the incidence of contamination
planning of a controlled clinical trial. When           and smear-positive culture-negative results. As
the plan is fully evolved, a protocol should be         regards drugs, assays are undertaken routinely
written up which contains all these points, and         on arrival, and if necessary at periodic intervals
made available to all participating physicians.         thereafter.
The protocol should be treated as a sacrosanct
document, and scrupulously observed in every            Evaluation of results
              9. Conduct of the study                      Even in the case of well-planned and well-
                                                                      10. Evaluation of results
   1. Strict adherance to protocol
           Reminder systems                              1. Be wary in excluding patients from analyses
           Deficiency-detecting systems                  2. Check for similarity between series in
                                                             (a) initial condition
   2. Design of forms and analysis cards
                                                             (b) intensity of examination during treatment
   3. Periodic abstraction of information
                                                         3. Objective methods to ensure bias-free comparisons
   4. Avoidance of bias in lab. investigations               (a) Independent assessor for x-ray reading
   5. Quality control—lab. tests, drugs                      (b) Clear definitions of fav. and unfav. response

                                                                         Ind. J. Tub., Vol. XVI, No. 2
46                                         S. RADHAKRISHNA

conducted studies, great care has to be taken in       ther, the x-rays should be fed to the assessor
the evaluation of the results. One common              in strict sequence of the patient serial number,
error is the exclusion of patients from final          which is by design a random sequence. Defini-
analyses. Sometimes, the reasons are obviously         tions of favourable and unfavourable response
unrelated to the treatment regimen; in such            must be clear-cut, and applied alike to all the
cases, it is sufficient to establish that the exclu-   patients regardless of the treatment regimen. In
sions have occurred to a similar extent in both        other words, classifying patients as having a
series. However, we have had examples at               favourable or unfavourable response on an
previous conferences where deaths from tuber-          individual basis without laying down strict
culosis were conveniently excluded and cheer-          definitions is a highly objectionable procedure.
fully optimistic conclusions drawn from the
findings in the survivors. Such procedures must            No evaluation can be complete without
be deplored strongly. The rule should be to            tests of statistical significance. However, the
describe the progress of all patients admitted         results of these tests must not be regarded as
to the study who belong to the population              giving proof of existence or proof of non-exis-
defined earlier (Slide 2).                             tence of a difference. Thus, when we say that
                                                       a difference is statistically significant, all that
    Although random allocation can be expec-           we mean is that the likelihood of it being a
ted to yield 2 series which are very similar in        fluke observation less than 5%.
their initial condition, nevertheless, analyses
should be undertaken to check that the 2                   I would like to stress that planning, conduct
series were in fact similar on admission. Also,        and evaluation are not three water-tight com-
analyses should be undertaken to check                 partments that can be dealt with independently
that the actual intensity of examination during        by different people or different committees.
treatment was the same.                                Atleast one individual, preferably the chief
                                                       investigator, must be deeply involved in all
   Finally, for assessing x-ray progress, it is        three stages, and all the other participants must
important to obtain the services of an indepen-        understand and appreciate the rudiments of
dent assessor who is not connected with the            controlled experimentation, if the outcome of
day-to-day management of the patients. Fur-            such efforts is to be valuable.

 Ind. J. Tub., Vol. XVI, No. 2
                                      G. S. ACHARYULU
                   (From Madanapalle Tuberculosis Research Unit, Madanapalle)
     Pulmonary Tuberculosis is the most com-           characteristics. In the latter situation, a sample
mon form among the different forms of tuber-           reasonably representative of the population is
culosis. The main indices useful in the                selected according to practical convenience
epidemiological study of this disease are the          for undertaking the survey. In the former
prevalence and incidence rates of (i) persons          situation, the population will have to be
infected with tubercle bacilli, (ii) persons           divided into a number of strata and a repre-
excreting tubercle bacilli and (iii) suspect cases     sentative sample will have to be selected from
of tuberculosis (diagnosis not confirmed               each stratum. An example of such a situation
bacteriologically). With the occurrence of             is provided by the presence or absence or non-
primary drug-resistant cases, knowledge of the         specific sensitivity in the population in a study
prevalence and incidence of such cases has             designed to investigate the protective effect
attained considerable importance.                      of BCG Vaccination, as there is reason to
                                                       believe that non-specific sensitivity offers some
     There are two types of epidemiological            protection against tuberculosis.
surveys, prevalence surveys and longitudinal
surveys. In prevalence surveys, the observa-               Special problems which are to be consi-
tions refer to a specific point in time. In            dered in planning experimental surveys are :
longitudinal surveys, the observations are repea-
ted at different points in time. Both prevalence          (i) incorporation of suitable ‘controls’,
and incidence rates can be estimated from                 (ii) method of randomization and
these surveys. They are useful for making
future projections of the tuberculosis problem           (iii) determination of the size of the experi-
and in evaluating the effects of different                     mental population.
tuberculosis control programme.
                                                            In situations, when there is doubt regarding
     Longitudinal surveys can be classified as         the effects of T.B. control measures or when
 experimental surveys and non-experimental             the interest is in evaluating their effects,
 surveys. The objective in experimental survey         ‘controls’ must always be introduced in the
 is to assess the value of or to compare the           experiment. If, on the other hand, there is no
 effects of different T.B. control programmes.         doubt regarding the effects of control mea-
 In non-experimental surveys, no such assess-          sures and the interest is only in comparing the
 ments or comparisons are contemplated.                effects of different control measures, there is
 Considerations in Planning the Surveys                no necessity for ‘controls’. If valid compari-
                                                       sons are to be made, the experimental units
     The first step in planning an epidemiologi-       (an experimental unit consists of a single
cal survey is to define the objectives of the          individual or any well defined group of indivi-
survey. This involves the specification of the         duals) should be randomly allocated to the
purpose of the survey and the epidemiological          different programmes. There are many methods
indices which are to be estimated, and how the         of randomization and they make use of the
survey results are going to be made use of.            knowledge, if available, of the inherent vari-
On the basis of these indices it will be deter-        ability of the experimental material which is
mined whether the survey should be a preva-            relevant to the investigation. The purpose of
lence or a longitudinal type.                          these methods is to increase the efficiency of
                                                       the experiments by reducing the experimental
    In experimental survey, the selection of the       error. The factors to be considered in the
individuals into the study depends upon the            choice of a proper method of randomization
type of population to which the experimental           are :
results are to be later applied. There are two
situations : the first is, the population is sup-           (i) the types of control programmes to be
posed or known to possess certain characteris-                  compared,
tics which will interact, favourably or unfavoura          (ii) available knowledge of the inherent
bly, with the T.B. control measures, which are to               variability of the experimental material
be compared in the experiments ; the second is                  and
when there is no knowledge about any such
                                                          (iii) practical considerations in the conduct
  * Paper read at the 24th National Conference on TB            of the survey such as actual process of
    and Chest Diseases held in Trivandrum in                    randomization etc.
    January 1969.

                                                                      Ind. J. Tub., Vol. XVI, No. 2
48                                       G. S. ACHARYTJLU

    Size of the experimental population will be            (i) reduction in the cost of the survey,
determined by making use of the estimates of
of experimental errors obtained from previous              (ii) the speed with which the estimates
surveys.                                                        can be obtained and
                                                          (iii) a greater accuracy in the results.
    There are two methods of undertaking
prevalence surveys or non-experimental                  Greater accuracy will be obtained as it will be
surveys ; complete survey method and sample         possible to control the various sources of errors
survey method. The objective in both the            in collecting the data by employing technically
methods will be to obtain knowledge of the          trained and experienced personnel, when the
distributions, aggregate or mean values of one      survey is conducted on a limited scale.
or more characteristics of a well defined popu-
lation. In complete survey method, observations        The undertaking of sample survey requires:
are made for every individual in the total
population, whereas, in sample survey method,               (i) the construction of a sampling frame,
observations are confined to a certain number
of individuals in the population. On the basis of         (ii) the choice of a sampling design and
the selection of the individuals, samples can be          (iii) the fixation of the sample size.
divided into random and judgement samples.
In random samples the individuals are selected           The sampling frame consists of a list of sam-
according to the laws of probability while, in      pling units in the total population without
judgement samples, selections are not done          omission and/or duplication and this is essential
according to these laws. The National Tuber-        for drawing random samples. The sampling
culosis Sample Survey, conducted during             unit may consist of an individual or all members
1955-’58, under the auspices of the Indian          in the household or a group of households in
Council of Medical Research, is an example of       a contiguous area or any other well defined
random sample survey. The European                  group. The sampling design stipulates the
Tuberculin Survey undertaken during 1965-’66        method of drawing the sampling units into
under the auspices of the International Union       random sample. For the same sample size,
Against Tuberculosis and the First Drug-            certain sampling designs will be more efficient
resistance Survey (1964-’65) conducted under        than others, efficient in the sense of containing
the auspices of the Indian Council of Medical       comparatively less sampling error. Although
Research are two examples wherein judgement         it is possible to minimize the sampling errors by
samples have been made use of.                      choosing efficient sampling designs and suitably
                                                    increasing the sample size, in practice, the deci-
      The random sampling method makes it           sion regarding the sampling design will have to
possible not only to estimate the population        be taken on the basis of the sampling frame
characteristics but also to estimate the errors     that is available and mainly in view of the
involved in those estimates. This method will       operational convenience of the field work. The
ensure that the samples will be representative      size of the sample will be fixed by the consi-
of the population. On the contrary, there is        deration of the cost of the survey and the
no guarantee that the judgement samples will        margin of error allowed in the estimates.
be representative of the population. Further,
the errors involved in the estimates of the         Types of Data collected
population characteristics cannot be estimated
from judgement samples. Another disadvant-              Specific data to be collected in any particular
age is, that it will not be possible to make        survey will be decided by the specification of
valid comparisons of the estimates obtained         the layout of the final statistical tables required
from one judgement sample with those                from the survey. The types of data that are
obtained from another. In view of these con-        generally collected in epidemiological surveys
siderations, random sample surveys are always       relate to (i) census, (ii) tuberculin tests, (iii) X-
to be preferred. Judgement samples should           ray examinations, (iv) bacteriological exa-
be made use of only if it is not possible, owing    minations, and (v) anti-tuberculosis measures.
to practical difficulties, to undertake random      A discussion of the considerations in collecting
sample surveys.                                     some of these data may be relevant here.
    With regard to the choice between random        Tuberculin Tests
sample surveys (hereafter referred to as sample
survey) and complete surveys, sample surveys           Although the importance of this test in
are always to be preferred as they have several     measuring the prevalence and incidence of
advantages over complete surveys. These are :       infection is well known, its value is restricted
 Ind. J. Tub., Vol. XVI, No. 2
                       PLANNING AND CONDUCT OF EPIDEMIOLOGICAL SURVEYS                                 49

by the use of BCG Vaccination. Hence, this                         as census taking, tuberculin testing
factor, that is, the extent to which the popula-                   etc.
tion concerned was covered by BCG Vaccina-
tion is to be considered before deciding to use              The instructions to the field staff should be
this test for measuring the epidemiological              unambiguous and should contain typical
indices.                                                 illustrations. If necessary, a pilot survey may
                                                         be undertaken. Such a survey will be useful
X-ray examinations                                       (i) in the development of the field procedures,
                                                         (ii) for testing the suitability of the various
    In countries like India, children in the             cards and forms designed and (iii) in giving
younger age groups constitute a considerable             training to the field staff.
proportion of the total population. In view of
the low prevalence and incidence of the disease              An important aspect, particularly in the
among children, it is sometimes desirable to             conduct of experimental surveys, must be
exclude them from these examinations. Such a             mentioned here. This is to ensure that groups
procedure will reduce the work-load consider-            of individuals allocated to different control
ably and at the same time the resulting loss in          measures to be compared are treated alike
precision of the estimates will be negligible.           thoughout the survey with regard to the admis-
Regarding the interpretation of X-ray films, a           sion of the individuals into the groups, inten-
suitable code to meet the specific requirements          sity of the diagnostic examinations and other
of the survey will have to be devised, as no             factors except the actual control measures.
internationally accepted code* has so far been           How any such factor can introduce bias into
evolved for this purpose. Two independent                the study may be illustrated by an example. In
readers are considered essential.                        a BCG Trial, if places injections are not
                                                         given to ‘controls’, it will not be possible to
Considerations in the conduct of the Survey              identify the group among the controls corres-
                                                         ponding to the group of persons who refused
    For the success of the survey, it is essential       BCG Vaccination. Another important aspect
to have well trained and experienced personnel.          is that the identity of the control measures
When such personnel are not available, recruit-          given to an individual should not be revealed
ment and training programmes will have to be             either to him or to those who will have to
undertaken well in advance. The various cards            assess the effects of control measures.
and forms to be used for collecting the data             Sources of Errors and Measures of Control:
should be designed. A detailed protocol for
the conduct of the survey should be prepared.                 In order to get valid and reliable estimates
This protocol should:                                    it is essential to minimize the errors which arise
       (i) Specify the purposes and objectives           from several sources. These are broadly divided
           of the survey;                                into sampling and non-sampling errors. Sampl-
                                                         ing errors occur only in sample surveys, whereas
                                                         non-sampling errors occur both in sample and
       (ii) define the populations to be                 complete surveys. While the sampling error, as
            surveyed;                                    mentioned earlier, can be kept within predeter-
                                                         mined limits by suitable measures, it will not
      (iii) describe the various methods of              generally be possible to identify all the sources
           examinations to be conducted along            of non-sampling errors and to estimate the
           with the criteria of classifications to       extent to which they affect the final estimates.
           be adopted;
                                                            Non-sampling errors arise on account of
      (iv) define the concepts to be used such           several factors and some of them are discussed
           as case of tuberculosis etc.;                 below :

       (v) contain detailed instructions to the              1. Failure to examine the complete study
           staff working in different sections such      population : This is called the error due to non-
                                                         response. One method suggested to obtain
      Efforts are being made by a specially appointed    unbiased estimates of the population characte-
      international committee (The Ad Hoc Commi-         ristics is to examine a random sample of
      ttee for the study of Classifications and Termi-   persons who failed to report for the examina-
      nology in Tuberculosis under the auspices of
      IUAT in cooperation with WHO), to evolve a         tions earlier. This procedure will not be
      code for interpretation which will be acceptable   practicable in many situations. The other way
      internationally and which will minimize the        of reducing this error is to minimize the percen-
      errors of interpretation.

                                                                         Ind. J. Tub., Vol. XVI, No. 2
50                                        G. S. ACHARYULU

tage of non-response by instensive efforts and to    used for this --purpose, provided that other
note down the reasons for non-response, so that      conditions are the same, comparison of esti-
an analysis can be made later to give an idea        mates from one group with another will be
as to how the estimates are going to be affected.    valid. But, when the interest is in estimating
                                                     the absolute value of the magnitude of infection
    2. Biases : There are two types of biases,       with tubercle bacilli, efforts should be made to
systematic and unsystematic. The occasional          evolve an objective criterion for this purpose.
failure to detect every bacillary case with single
spot sputum specimen is an example of syste-             4. Errors in data processing and tabulation:
matic bias. Such a procedure will lead to            These errors can be reduced by giving clear
consistent under-estimation of the number of         instructions, by employing well trained staff
bacillary cases. The extent of under-estimation      and by exercising constant supervision over
can be ascertained by conducting special studies     them.
or from the results of such studies made
elsewhere. If the resources permit, this error           To sum up, the first step in planning a
can be reduced by better methods of sputum           survey is to provide a clear and unambiguous
collection.                                          statement of its purposes and objectives.
                                                     Planning requires consideration of all important
    The effect of unsystematic bias is sometimes     aspects of the survey, many of which are inter-
over-estimation and some times under-estima-         dependent. The application of statistical
tion. The unconscious preference for round           methods is essential to get valid and reliable
numbers, generally observed in reading the           estimates and for making valid comparisons.
tuberculin reactions and in reporting the ages,      Recognition of the types of errors which might
may be given as examples of unsystematic             occur in survey will not only lead to better
biases. The effects of these errors can be           planning and execution of the survey, but also
reduced to some extent, by suitably grouping the     to better understanding of the reliability of the
observations in preparing the frequency distri-      estimates obtained from the survey.
bution when the data are tabulated.
    3. Errors in classification : Generally,           1.   WHO Expert Committee on Tuberculosis, 8th
tuberculin positive reactors who are supposed               Report, 1964 WHO Technical Report Series,
to have been infected with tubercle bacilli are             No. 290.
denned to be those whose reactions exceed a
certain size, for example 6 mm. or 8 mm. The           2. Protocol of the Coordinated European Tuber
dividing point between negative and positive              culin Survey, Bull. WAT, 1965, No. 1, Vol. 36,
reactors varies from one study to another and
maybe anywhere between 6 to 15 mm. This                3. Report of the Committee on Epidemiology and
type of definition is known to involve two                Statistics, Bull. WAT, 1966, No. 1, Vol. 38, 71-74.
types of errors, viz., inclusion of persons who
have been actually infected with tubercle              4. Gangadharam, P.R.J., Proceedings of the 21st
bacilli and exclusion of persons who                      Tuberculosis & Chest Diseases Workers’
have been actually infected with tubercle                 Conference, 1966, 104-112.
bacilli. The magnitude of these two types of
errors depends upon the magnitude of the               5. Report of the Ad Hoc Committee for the study
prevalence of non-specific sensitivity in the             of Classification and Terminology in Tuberculo
community. As long as the same definition is              sis, Bull. WAT, 1965, No. 1 Vol. 36, 55-72.

 Ind. J. Tub., Vol. XVI, No. 2
                        ANALYSIS AND PRESENTATION OF DATA*

                                        G. P. M ATHUR
                         (From New Delhi Tuberculosis Centre, New Delhi)

     Assuming that a clinical trial, laboratory      valid if experiments, surveys etc. have been
experiment, or epidemiological survey has been       properly designed and all the rules observed.
concluded and a mass of reliable data collected,     The most important are the ones concerned
there arises the question of analysis, interpre-     with random allocation and the elimination of
tation and presentation. The vast quantity of        bias ; and with advance planning they are not
information has to be numerically summarised         difficult to comply with.
and logically tenable conclusions drawn there-           Statistical data usually are affected by a
from. The statistical techniques for dealing         multiplicity of causes and this is more so in the
with data are determined largely by the plan of      case of biological data. For drawing valid
the study and the nature of the information          conclusions from data influenced to such a
collected. Analysis, in the main, is a job for       marked degree by variation and chance, there
the statistician and, as a rule, doctors and         exist powerful statistical tools. These are based
medical research workers need not aim at mas-        on laws of probability and that is why conclu-
tering the statistical methods applicable to         sions drawn thereby, though not applicable to
different situations However, an understanding       individuals, are true over large numbers of
of the genera] principles does help in the sys-      individuals. A special advantage of the statisti-
tematic compilation of the right type of data,       cal technique is that it furnishes estimates of
in intelligent discussion with those who are         the precision of the results obtained.
mainly concerned with the statistical evaluation         It would be obviously impossible within the
and in interpreting the final results. Indeed, it    short space of this paper to describe or even
is only a continuation of the process, starting      outline briefly the various forms of statistical
at the planning stage, whereby the medical           treatment of data pertinent to different situa-
research workers and statisticians learn to          tions. As already stated, these are to a large ex-
understand each other’s language and arrive at       tent determined by the nature of the studies. I
a common basis for discussion.                       would therefore content myself with a few gene-
     It would be useful to start at the point        ral remarks.
where data are being collected and compiled.             Interpretation of biostatistical data is not
Except for large scale surveys, it is not really     merely a question of applying certain mathe-
essential in most cases to resort to mechanical      matical formulae and obtaining a result.
sorting and tabulation. Indeed, for studies          Even more important than these are an exercise
involving a few hundred cases it is sometimes        of one’s logical and critical faculties. Medical
more advantageous to have either individual          journals are replete with instances where the
cards or even simple lists. The latter, prefer-      wildest conclusions have been drawn by apply-
ably prepared in code, and incorporating all         ing statistical techniques contrary to the dicta-
information, are in fact to be particularly reco-    tes of commonsense and elementary logic. Even
mmended for small scale studies, since they          such apparently simple things as percentages,
permit an intimate acquaintance with the data,       prevalence and attack rates can be dangerous
suggesting possible relationships between vari-      in the hands of persons not accustomed to look
ous characteristics and, in general, indicating      at figures in a critical way. Special care needs
the lines along which data should be analysed.       to be exercised when conclusions are being
     The form in which these entries are to be       drawn on the basis of a comparison between
 made itself needs to be carefully designed,         two groups. Unless it is ensured that the
 special attention being paid to such matters of     groups are similar in all respects, except the
 detail as units to be used, grouping of data        one under study, conclusions will not be valid.
 and and above all to comprehensiveness.             In many cases, the methods of random alloca-
 Simplicity, precision and legibility and other      tion would have taken care of such differences.
 criteria which should be kept in mind.              In others one may have to resort to ‘standardi-
     The importance of associating the statisti-     sation’ to nullify the effect of inequalities in
 cian with any research project from the very        important respects.
 start has already been stressed. Data collected         Tests of significance are so widely used by
 without any plan or with a defective plan may       statisticians and so often misunderstood by
 not lead to any worthwhile conclusions. Tests       others that it is probably useful to say a word
 of significance and statistical analysis are only   about these. As an example, let us consider a
  *Paper read at the 24th National Conference on simple clinical trial in which a group of 100
TB & Chesl Diseases held in Trivandrum in Jan. 1969. patients has been divided at random into two
                                                                    Ind. J. Tub., Vol. XVI, No. 2
52                                          G. P. MATHUR

sub-groups, those in the first group getting           the nineteen forties were to be compared with
drug regimen A and those in the other, drug            those of a similar sample from recent years
regimen B. Assume further that at the end of a         by a panel of readers. Some x-rays in the
certain period, sputum conversion rates of             former sample could not be traced, which
70% and 80% have been observed in the two              fact tentatively was ascribed to faulty storage.
respective groups. How are we to know whe-             Since no bias was suspected, it was decided to
ther the observed difference represents a real         go ahead with the comparison of the available
superiority of regimen B over regimen A or is          x-rays. This revealed a rather surprising
merely due to chance ? This is done by using a         finding: that contrary to the general impression
test of significance. To start with, we set up         there were not many cases with far advanced
what is known as the ‘null hypothesis’. In our         disease in the older series. Further scrutiny
particular example, for instance, we begin by          brought out the fact that in the 1940s, it was
assuming that the two drug regimens do not in          not considered worthwhile in the New Delhi
fact differ in respect of sputum conversion. We        TB Centre to take x-rays of cases with very far
then calculate the mathematical probability of         advanced disease. Because of the wartime
getting a difference at least as big as the one        scarcity of x-ray films, and the comparatively
observed if the ‘null hypothesis’ was correct. If      poor prognosis of such patients, they were
this probability is sufficiently low, say 5% or        usually diagnosed by fluoroscopy and sputum
less, we reject the null hypothesis and conclude       examination, no permanent x-ray record being
that the observed difference is in fact real. It       considered necessary. Obviously, further
must however be remembered that, based on              analysis of this data had to get round this
the laws of probability as it is, the test of signi-   difficulty. Pitfalls like this are not at all rare
ficance cannot be said to have ‘proved’ the            in analysis of unplanned data and the investi-
existence of a real difference. All it says is         gator has to make assurances doubly sure
that the differences are very unlikely to have         before drawing any conclusions. For this and
arisen by chance. Likewise, a ‘not significant’        other reasons, retrospective studies should not
decision does not ‘prove’ the absence of any           be undertaken as an easy way out when
real difference ; it only means that the observed      properly designed prospective studies are
difference could well arise by chance alone.           possible and feasible.
Incidentally, it is also possible for a difference
to be statistically significant, and yet unimpor-       After the completion of analysis, findings
tant. Provided a sufficiently large number of       have to be presented either in the form of a
patients has been included in the trial, differ-    paper in a journal or as a personal communi-
ence between sputum conversion rates of 70%         cation to a scientific conference. The technique
and 72% in two drug schedules may well turn         of writing research papers is not really difficult
out to be statistically significant. Yet the differ-to acquire. Papers, above all, should be read-
ence is so slight that it may not be worth          able and simplicity should be aimed at, even if
bothering about and the medical worker may          it needs a special effort. The question of the
well be justified in preferring the schedule with   size and number of tables and charts is impor-
70% conversion if it has other advantages.          tant, as we will presently discuss, but no less
                                                    important is that of a lucid exposition in the
     Considering the stress Lald on proper plan- text. Indeed, the finest papers are those where
 ning of studies, one might well get the impre- tables etc. do not impede the line of reasoning
 ssion that studies on unplanned data are, at and can even be dispensed with for a prelimi-
 best, a waste of time. This, however, is not minary reading.
 always true. Retrospective studies necessarily
 have to deal with unplanned data and may be            It is difficult to lay down any rules regar-
 inescapable in many cases. The analysis of Data ding the number of tables and diagrams but
 from such studies however is a very complex too liberal a use of these certainly gives rise to
 task. It is necessary to scrutinize the data in a sort of ‘consumer resistance’. There is also the
 detail to eliminate possible source of bias. It is danger that with too many tables and charts-
 not unusual that a finding which appears plausi- one may be unable to see the wood for the
 ble on the face of it may turn out to be un- trees. In general, tables in the text should be
 warranted on closer examination. Spurious brief and purposeful; the subsidiary ones are
 associations in particular have to be guarded better relegated to the Appendix. Each table
 against. An example may be worth quoting should be complete in itself, i.e., relevant
 here. Some years back we at the New Delhi information such as abbreviations and units
 TB Centre were interested in finding out whe- used, period covered, whether a certain rate is
 ther the pattern of tuberculous disease had per cent or per thousand, or per thousand per
 changed materially over the years. To this year, etc. should be given, within the table if
 end, x-rays of a sample of cases reporting in possible, in footnotes if necessary. Graphs,
     Ind. J Tub , Vol. XVI, No 2
                             ANALYSIS AND PRESENTATION OF DATA                                    53

bar diagrams etc. are sometimes very useful         presentation has to be judiciously pruned.
for driving home a point but their use as a         Only the most important tables and diagrams
routine or as a substitute for tabular data is to   can be presented. These, again, should be as
be avoided. Serious minded readers sometimes        simple as possible, each single slide containing
want to make some additional calculations on        only the minimum quantity of figures needed
their own and only tabulated data rather than       to make a point. It must be remembered that
sterile diagrams can serve this purpose.            the human eye can take in only a limited
                                                    quantity of statistical data at a time— spe-
    Having made a plea for brevity, it now          cially when each slide is projected for just
remains, paradoxically, to enter a caveat about     about 30 seconds. If too much mental effort
the dangers of going to the other extreme.          is required to study a table or follow an
Instances are not rare of papers—and I mean         argument many in the audience would rather
papers with a statistical aspect—published with     give up. Since it is the speaker who is prima-
the sketchiest of data. Quite often, the idea at    rily interested in ‘selling’ his paper, it is for
the back of the mind is that figures are boring     him to forestall audience apathy.
things and ‘let us get them over while the fit is
on us’. This suggests a casual, almost frivo-           I am quite conscious that it is no easy task
lous, attitude to the whole business of research    for most clinicians to work up any enthusiasm
and only the uncritical can be taken in by such     for figures and statistical methods. It will not
logic. The discerning reader is apt to ascribe      be a bad beginning if these are accepted even
lack of relevant data to ignorance of the           as a necessary evil. For, in the words of
research discipline, or worse.                      Bradford Hill, “In both clinical and preventive
                                                    medicine, and in much laboratory work, we
     What has been said so far refers specially     cannot escape from the conclusion that they
 to papers meant for publication. Further           (figures) are frequently cogent, that many of
 problems arise when a paper has to be presen-      the problems we wish to solve are statistical
 ted in a conference instead of being printed in    and that there is no way of dealing with them
 a journal. As the time is limited, material for    except by the statistical method”.

                                                                   Ind. J. Tub., Vol. XVI, No. 2

                  K. L. AGRAWAL , S. NARASIMHA RAO and D. P. AGRAWAL
                         (From Kasturba Medical College, Mangalore.)

Introduction                                         5 ml. of blood was collected and allowed to
                                                     clot at room temperature. In most cases the
    Reversal of serum albumin-globulin ratio         sera were subjected for analysis, when it was
in a wide variety of diseases caught the fasci-      not possible to analyse on the same day the
nation of research workers and gave them an          sera were kept frozen till they were analysed.
impetus to penetrate into the intricate
mechanisms, if any, involved. Much break-                Total serum proteins were estimated by the
through was made since a number of earlier           biuret method of Kingsley (1942). Electro-
workers reported such a reversal in pulmonary        phoresis was done according to the method
tuberculosis employing the conventional              described by Giri (1956). The electrophoreto-
techniques of salt fractionation then in vogue       gram so obtained was scanned by photoelectric
(Eichelberger & McCluskey, 1927 ; Gutman             densitometer. A graph was constructed with
et at 1936 ; & Bing, 1940) The development           the densitometric readings as the abscissa and
of electrophoretic technique of serum protein        the distance in millimeter as the ordinate
fractionation by Tiselius in 1937 brought in a       (Fig. 3 and 4). Alpha-1 globulin moved
revolutionary change in the concept of               almost along with the albumin fraction, there-
albumin-globulin ratio reversal and afforded         fore it was included in the albumin value.
the research workers a more meaningful tool          The exact concentration of each protein
to understand the complex field of protein           fraction was then obtained from the total
biosynthesis and protein alternations in health      protein value.
and diseases. Luetscher (1941) was the first to
report electrophoretic studies in pulmonary             E.S.R. for the first hour was estimated by
tuberculosis. He found decreased albumin,            Westergren’s method. The presence of C-
increased alpha and gamma globulin levels in         reactive proteins was qualitatively determined
his cases. By and large it appears that              by slide-latex fixation test using latex anti C-
increase in alpha-2 globulin is the characteristic   reactive protein reagent manufactured by
finding in pulmonary tuberculosis, although          Hyland       Laboratories,     Los     Angeles,
observations regarding alternations in the           California, U.S.A. The test was performed as
other protein fractions are conflicting. The         per directions provided with C-reactive
present study was undertaken to study the            protein kit.
changes in serum proteins in pulmonary
tuberculosis employing agar electrophoretic          Results
technique and to correlate, if possible, the
protein fractions with E.S.R. and C-reactive             Electrophoretic serum protein values, E.S.R.
protein value.                                       and C-reactive protein values of the 33 tuber-
                                                     culosis patients and 20 normal controls are
Materials and Methods                                presented in Table I—III. The mean total
                                                     protein value of 33 tuberculosis cases is
    Thirty three patients attending the Wenlock      5.597±0.446 (S.E. Mean 0.079) and that of
Hospital, Mangalore, were selected for the           the normal controls is 6.245±0.647 (S.E. mean
present study. The pulmonary lesions were            0.148). Statistical analysis of the values
subdivided into minimal (referred to as early        revealed that the decrease in the total protein
by us) and moderately advanced (referred to as       values in tuberculosis is highly significant with
advanced by us) in accordance with the               a ‘t’ value of 4.225 (Table I). The observed
classification of National Tuberculosis Asso-        decrease of the mean albumin value in the
ciation. All the patients came from the low          tuberculosis patients as compared to the
middle class and lower classes of society.           normal controls is not statistically significant.
Their nutritional status was low. No attempt         Similarly the apparent increase in the average
has been made to group the cases according           A/G ratio and the decrease of albumin/alpha-2
to age, or sex because of the small number of        globulin ratio of the tuberculosis patients over
subjects. A group of twenty normal blood             the corresponding average values for the
donors has been included to serve as control.        normal group is not statistically significant.
                                                     However, the increase in alpha-2 globulin value
    On the morning of the day of the test,           and the decrease in beta and gamma globulin
 Ind. J, Tub., Vol. XVI, No. 2
              AGAR ELECTROPHORESIS OF SERUM PROTEINS IN PULMONARY TUBERCULOSIS                                        55
                                                       TABLE 1

                 Mean and standard deviation of protein and electrophoretic values of 33 Tuberculosis
                                          patients and 20 normal controls

                                            Tuberculosis cases     20 Normal controls        Difference in means of
                                                                                             patients and controls

 Total Protein                     Mean           5.597                  6.245                    —0.648**
                                   S.D.           0.446                  0.647
                                   S.E.           0.079                  0.148                    (t=4.225)

  Albumin                          Mean           2.836                  3.050                    -0.214 N.S.
                                   S.D.           0.661                  0.237
                                   S.E.           0.117                  0.055

  Alpha-2 Globulin                 Mean            0.963                 0.580                    0-383**
                                   S.D.            0.415                 0.415                    (t=3.524)
                                   S.E.            0.082                 0.033

 Beta-Globulin                     Mean           0.517                  0.830                    —0.3134**
                                   S.D.           0.318                  0.168                    (t=4.727)
                                   S.E.           0.056                  0.037

  Gamma-Globulin                   Mean            1.280                 1.735                    —0.455**
                                   S.D.            0.517                 0.504                    (t=3.411)
                                   S.E.            0.076                 0.116

  A/G Ratio                        Mean            1.167                 0.977                   0.190 N.S.
                                   S.D.            0.626                 0.165
                                   S.E.            0.111                 0.038

  Albumin/Alpha-2                  Mean           4.313                 5.500                    — 1.187 N,S.
  ratio                            S.D.           3.626                 0.987
                                   S.E.           0.641                 0.226

         Note :            N.S. — Not significant
                           **    — Highly significant P 0.01
                           The t — Test for the difference of means is used in all these.

values of the tuberculosis patients compared to              culosis group. No statistical significance has
the normal group is highly significant with ‘t’              been observed using the ‘t’ test.
values of 3.524, 4.727 and 3.411 respectively.
    Statistical analysis of the E.S.R. and elec-                 Fig. 1 depicts the E.S.R. values of the T.B.
trophoretic protein fraction of the 25 advanced              patients with positive and negative C-reactive
and 8 early cases have been presented in table               protein. Fig. 2 indicates the total protein
II with a view to find out whether it is possible’           values of the T.B. patients with positive and
to assess the severity of disease as classified.             negative C-reactive protein values. As eviden-
It can be seen from the table that except                    ced from the diagrams there is no cluster of
albumin/alpha-2 globulin ratio all other find-               points at any place ; both the positive and
ings show statistically insignificant variation.             negative values are scattered and hence statisti-
In the case of albumin/alpha-2 globulin ratio                cally insignificant. Similarly no significant
early cases of tuberculosis have a mean value                correlation could be obtained when positive
of 5.314±5.116 with a ‘t’ value of 2.767. This               and negative C-reactive protein cases were
increase is highly significant.                              correlated with other electrophoretic protein
    In table III are given the mean values of                fractions. Figs. 3 and 4 show the typical
E.S.R. and electrophoretic protein fractions                 electrophoretograms obtained for a normal
for the 24 C-reactive protein positive and 9                 and tuberculosis serum. The results have been
C-reactive protein negative cases of the tuber-              summarised in table IV.
 Ind, J. Tub., Vol. XVI, No. 2
56                     K. L. AGRAWAL, S. NARASIMHA RAO AND D. P. AGRAWAL

                                                    TABLE   II
     Mean and standard deviation of E.S.R., total protein and electrophoretic values of Tuberculosis patients

                                           Mean ± standard deviation of                  Difference in mean of
                                                                                         advanced and early
                                   25 advanced      8 early cases     ‘all 33 cases

 E.S.R. (m.m. for 1st hour)          88.44            78.62              86.06              9.82         N.S.
                                    ±23.976          ±28.115            ±25.349

 Total Protein (gm%)                  5.652            5.425             5.597              0.227        N.S.
                                     ±0.433           ±0.444            ±0.446

 Albumin                              2.804            2.938             2.836             -0.134         N.S.
                                     ±0.653           ±0.675            ±0.661

 Alpha-2 Globulin                     0.965            0.955             0.963              0.010        N.S.
                                     ±0.441           ±0.532

 Beta Globulin                        0.567            0.360             0.517              0.207        N.S.
                                     ±0.334                             ±0.318                                       •e*
                                                      ±0.182                                                          I,

 Gamma Globulin                       1.3140           1.173             1.280              0.141        N.S.
                                     ±0.469           ±0.292            ±0.517

 A/G ratio                            0.105            1.361             1.167              -0.256        N.S.
                                     ±0.591           ±0.689            ±0.626

 Albumin/A lpha-2                     3.993            5.314             4.313               -1.321        **
 ratio                               ±2.923           ±5.116            ±3.626                          (t =2.767)

           Note :         N.S. — Not significant
                          **   — Highly significant: P 0.01

Discussion                                                     It is believed that in most of the infectious
                                                            diseases there is a reversal of the albumin-
    Intensive study of the distribution of serum            globulin ratio. Our results in pulmonary
proteins in tuberculosis has received the                   tuberculosis do not subscribe to such a belief.
attention of many workers. Evidence has been                Agar electrophoretic study of the serum protein
established that in “active infection”, signifi-            changes in our series has shown that there is
cant changes in serum proteins occur.                       no statistically significant decrease of albumin
Gaitonde et al (1959) and Bovornkitti (1962)                value in tuberculosis patients compared to
have reported a fall in total protein level in              normal or between advanced and early cases.
pulmonary tuberculosis. We have observed
a similar fall in our cases of pulmonary tuber-                 The most striking finding of our results is
culosis. The decrease in our series of 33 cases             the abnormality found in the globulin fractions.
when compared with normal group is highly                   Raised levels of alpha-2 globulin has been the
significant with a ‘t’ value of 4.225 (Table I).            most consistent finding. This observation is in
This indicates poor nutritional status of tuber-            confirmity with those of others (Gaitonde 1959,
culosis patients. The fall in total protein                 Bovornkitti 1962, Seibert 1942, Volk 1953, &
levels has been reported to be progressive from             Gilliland 1956). The increase in alpha-2
minimal to advanced cases (Bovornkitti 1962).               globulin fraction represents tissue destruction
However, this fall in our series is not progres-            (Seibert 1947) and therefore it can be said that
sive since the value in early cases is 5.425 gs%            pulmonary tuberculosis sets in tissue destruc-
whereas, in advanced cases it is 5.652 gs.%.                tion in the host. This is so even in early
 Ind. J. Tub., Vol. XVI, No. 2

                                                       TABLE       III
      Mean and standard deviation of the protein and electrophoretic values of T.B. cases with positive
                                      and negative C-reactive protein

    Characteristic Studied              C-Reactive Protein Positive                         C-Reactive Protein Negative
                                        (24 values)                                           (9 values)

                                          Mean             Standard deviation                Mean       Standard deviation

E.S.R. (mm for 1st hour)                  86.38                          27.14              85.22                    23.21

Total Protein                              5.538                          0.438               5.756                   0.429

Albumin                                    2.729                         0.576               3.122                   0.777

Alpha-2 Globulin                           0.981                         0.467                0.916                   0.454

Beta-Globulin                              0.563                         0.316               0.393                   0.285

Gamma Globulin                             1.267                          0.471               1.314                   0.309

A/G. ratio                                 1.068                         0.540               1.432                   0.750

Albumin/Alpha-2 ratio                      3.948                          3.041              5.287                   4.745

        For each of the characteristic studied above the difference between the mean of positives and of
negatives is found to be NOT SIGNIFICANT by using t — tests
        There is no correlation between the C-reactive protein and any of the above characteristics.

                                                       TABLE       IV
                                     Table showing summary of the results

                                                                                                        A/G. ratio





Pulmonary T.B. total number of cases
compared with normal

Pulmonary T.B. early cases compared
with advanced cases

Pulmonary T.B. advanced cases
compared with early cases

          Continuous and broken arrows show significant and insignificant direction of alteration respectively.

                                                                                       Ind, J. Tub., Vol. XVI, No. 2
58                 K. L. AGRAWAL, S. NARASIMHA RAO AND D, P. AGRAWAL

                     Fig. I                                           Fig. II

                     Fig. Ill                                         Fig. IV
 stages of the disease. The stage of the disease   in the early stage of the lesion (table I). This
 process, however, cannot be definitely assessed   observation is not in confirmity with the find-
 since there is no correlation in our series       ings of other workers who observed a signi-
 between the values and the severity of the        ficant elevation of beta globulin fraction in
 lesions.                                          severely ill patients (Gaitonde 1959, Volk
                                                   1953, Seibert 1947). However, Baldwin and
    Beta globulin values tend to fall in tuber-    Hand (1953) have also observed a decrease in
 culosis group as compared to the normal           the beta globulin component. Since the increase
 group. The decrease is significant with a ‘t’     of beta globulin is generally associated with
 value of 4.727. The decrease is more marked       liver damage, the differing observations may
  Ind. J. Tub,, Vol. XVI, No. 2

  not be ascribed primarily to pulmonary tuber-      Summary
  culosis. Further work is necessary to impli-
  cate elevated beta glubulin as a secondary             Fractionation of serum proteins by agar
  effect of pulmonary tuberculosis or otherwise.     electrophoresis has been done in 20 normal
      There is significant fall of gamma globulin    controls and 33 patients of pulmonary tuber-
 fraction with a ‘t’ value of 3.411. This finding    culosis prior to treatment with anti-tuberculosis
 is not in agreement with other workers who          drugs. The results clearly demonstrate that
 have all reported an increase of this fraction in   there are definite changes in serum proteins
 all cases of active pulmonary tuberculosis.         from normal values in tuberculosis. A signi--
 Seibert et al (1942) have ascribed the rise to be   ficant fall in total proteins, beta and gamma
 an indication of resistance to the disease. It is   globulins and a rise in alpha-2 globulin has
 generally known that increased gamma                been consistently observed. Albumin/alpha-2
 globulin is a common characteristic of most         globulin ratio in advanced cases has been
 hepatic disease (Agarwal 1957, & Popper 1951)       found to be significantly lower than that of
 and that liver impairment is present in             early cases.
 advanced tuberculosis (Hurst 1947, & Small                    ACKNOWLEDGEMENT
 1950). Accordingly the elevation found by
 other workers could partly be expLalned by             The authors are thankful to Dr. M.V.
 liver alteration. Since our series did not          Chari, Principal, Kasturba Medical College
 include far advanced cases, it is likely that       for permission to publish this paper and to
 they did not have associated liver alteration.      the Department of Biostatistics, Christian
 Since our series did not include far advanced       Medical College, Vellore for statistical analyses.
 cases, it is likely that they did not have
 associated liver alteration. However, the                                REFERENCES
 significantly low value obtained by us remains       1.    Agarwal, K.L., Kumar, A. Kumar, S,, and
 to be expLalned.                                           Mangalik, V. S. (1957) J. Ind. Med. Assoc., 29
     The clinical status is better correlated with          (10), 387.
albumin/alpha-2 globulin ratio and it is con-         2.    Baldwin, R.W.. and Hand, C.N. (1953) Amer.
sidered to be a better criterion of the severity              Rev. Tuberc. 68, 372.
of the disease process. We have also observed         3.    Bing, J., (1940) Acta. Med. Scandinav, 103, 547.
albumin/alpha-2 globulin ratio fall in tuber-         4.    Bovornkitti, S., (1962) Amer. Rev. Resp.
culosis when considered as a whole. But this                 Diseases, 85, 58.
alteration is not statistically significant. How-      5.   Eichelberger, L., and McCluskey, K.L. : (1927)
ever, there is a definite and significant fall of            Arch. Int. Med., 40, 831.
this ratio in the advanced stage of the disease       6.      Gaitonde, B.B., Shinde, A.G. and Rao G.S. :
(Table I). Thus our observation is in confir-                (1959) Ind. J. Tub. 6, No. 1, 12.
mity that the albumin/alpha-2 globulin ratio          7.     Gilliland, I.G., Johnstone, R.N., Stradling,
is a better criterion of the severity of the
disease process as observed by other workers.                P. and Abdelwaheb. E.N. : (1956) Brit. Med. J.
                                                             1. 1460.
     That E.S.R. value cannot be correlated
with the protein fractions and the severity of        8.     Giri, K. V. : (1956) J. Lab. Clin. Med, 48,
the disease is evident from Table II. Our                    No. 5, 775-778.
findings are in agreement with Gaitonde               9.     Gutman, A.B., Gulman, E.B., Jillson, R., and
(1959), & Gilliland (1956) that correlation of               Williams. R.D. (1936) J. Clin. Investigation, 15,
the clinical status with albumin/alpha-2                     475.
globulin ratio is a better index than with            10.    Hurst, A., Maier, H.N., and Lough, S.A. : (1947)
E.S.R.                                                       Amer. H. Med. Sci. : 214, 431.
     Although biochemical study of the alter-         11.    Kingsley : (1942) J. Lab. Clin. Med., 27, 840.
ation of the serum protein fractions in pulmo-               Luetscher, J.A. Jr., (1941) J. Clin. Invest., 20,
nary tuberculosis alone do not prove to be of                99.
diagnostic value, they will fruitfully assist in      12.   Popper, H., Bean, W.B., De La Huerga, J.,
establishing the therapeutic efficacy and the               Franklin, M., Tsumagari, Y., Routh. T.I. and
                                                            Stiegmann. F., (1951) Gastroenterology, 17, 138.
severity of the lesion. “The protein spectrum
in plasma and serum is the resultant of a host        13.    Seibert, F.B., Seibert, M.V., Atno, A.J. and
                                                             Campbell. H.W. : (1947) J. Clin. Invest., 26, 90.
of factors concerned with the formation, the          14.    Seibert, F.B., Nelson, J.W., (1942) J. Biol.
interaction, and the destruction of the indivi-              Chem. : 143, 29.
dual components”. It remains, however, to             15.    Small, M.J. : (1950) Amer. Rev. Tuberc. 61, 893.
be established what interplay of mechanisms                  Teselius, A., (1937) Biochem J., 31, 1464.
are responsible for the alterations in the            16.    Volk, B.M., Salfer, A., Johnson, L.E., and
different globulin fractions.                                Oreskes, I. (1953) Amer. Rev. Tuberc., 67, 299.

                                                                      Ind. J. Tub., Vol. XVI, No 2
                         AND THE ELDERLY PATIENTS
                                         R. K. NARANG
                          (From G. S. V. M. Medical College, Kanpur)
Introduction                                        were included in the study. Moribund patients
                                                    were excluded from the trial.
    A combination of streptomycin and isonia-
zid is very effective in the initial treatment of       Sputum was examined for AFB using the
pulmonary tuberculosis. However, strepto-           Ziel-Neelson technique. Only smear positive
mycin, since it is given by injection, has          cases were included. As the culture facilities
obvious drawbacks in ambulatory therapy.            in the department are inadequate and unreli-
There are villages where the patients have to       able, no culture examination was done. Smear
walk miles to get their daily injection. The        examination was repeated once a month and,
charge for injection adds to the cost of treat-     if found negative, further specimens were
ment. Again, streptomycin is not a very suit-       examined on three consecutive days. If no
able drug for the middle aged and the elderly       AFB were demonstrable in all the specimens,
patients due to high incidence of vestibular and    the case was adjudged as bacteriologically
cochlear toxicity.                                  negative. If bacteriological conversion was
                                                    not obtained at four months and especially
    Encouraged by the report of British Tuber-      if there was also evidence of clinical or radio-
culosis Association/Hong Kong Tuberculosis          logical deterioration, the case was withdrawn
Treatment Services (1964) on ethionamide and        from the study, having been adjuged as treat-
isoniazid in newly diagnosed previously un-         ment failure.
treated cases of pulmonary tuberculosis, it was
decided to assess the role of this combination          A chest radiograph was taken in the begin-
in the middle-aged and the elderly cases of         ning in every case to assess the extent and
pulmonary tuberculosis.                             type of the disease. Only moderately advanced
                                                    or far advanced cases were selected for the
Material And Methods                                trial ; minimal cases were excluded as excellent
                                                    results have been reported with isoniazid alone
       The material for the present study con-      in such cases. The skiagram was repeated
sisted of 50 cases of pulmonary tuberculosis        every three months and at the time of sputum
whose ages ranged from 50 to 85 years               conversion.
(average 62 years). 44 were men and 6
women. 2 cases were, however, withdrawn                 All the patients were unhospitalized
from the trial as they were found to have had       throughout the course of their treatment.
previous treatment with anti-tubercular drugs.      They collected drugs for one week in the first
Another 3 cases were withdrawn early in the         instance and if no side effects to the drugs were
trial as they did not stick to the protocol ; a     compLalned of, they were supplied drugs for a
totally oral regime did not appeal to them and      fortnight at a time.
they were getting streptomycin injection from
other sources.                                          On each visit the progress was assessed
                                                    clinically ; radiographs and sputum examina-
    All the cases were placed on 400 mg.            tions were ordered as outlined above. Any
isoniazid and 500 mg. of ethionamide daily          symptoms or signs suggestive of drug toxicity
given as a single dose at bed time. Isoniazid       were noted ; to avoid suggestion no attempt
was given as four 100 mg. tablets and ethion-       was made to elicit symptoms by direct ques-
amide as four 125 mg. sugar coated tablets.         tioning.
Although higher strength ethionamide tablets
are also available, 4 tablets of each drug was      Observations And Results
thought to lessen the chances of misunder-
standing about instructions. It was proposed            As mentioned above 5 cases were excluded
to continue the combination for one year. The       early in the trial due to various reasons. Thus
drugs were supplied free of cost to the             only 45 cases were assessed. Of these 23 had
patients.                                           moderately advanced disease and 22 had far
                                                    advanced lesion. 12 cases also suffered from
   The patients were closely questioned about       chronic dyspepsia, 3 had diabetes mellitus (1
the history of previous treatment, if any. Only     with neuropathy and nephropathy also) and 4
those who had not received any specific therapy     had history suggestive of chronic bronchitis.
 Ind. J. Tub.. Vol. XVI, No. 2
          ETHIONAMIDE AND ISONIAZID IN THE MIDDLE-AGED AND THE ELDERLY PATIENTS                                        61

A. Efficacy of Treatment (Table Nos. 1 & 2)                                   TABLE 1

    Of the 45 cases, 2 cases had to be with-                     Showing the results of treatment
drawn due to intolerance to the drugs (pre-                        Total number of cases—43
sumably to ethionamide), so that efficacy                                          No. of cases Percentage
of treatment was assessed in 43 cases only.
    Clinical improvement, as shown by relief          Clinical improvement              42             97.6
in chest symptoms and toxemic manifestations
were noted in 42 out of 43 cases. 3 of these          Radiological improvement          42             97.6
deteriorated later.
                                                      Bacteriological conversion        39               90.0
    All the cases had cavitary disease on
admission to the trial. In 97.6% there was
radiographic improvement, assessed by clearing                                TABLE 2
of shadows and/or dimunition in size of the
cavities. In 31 cases (72%) cavities dis-                 Showing the bacteriological response in relation
                                                                        to extent of disease
appeared completely while in others they were
markedly reduced in size. The maximum                                 Total number of cases—43
improvement was noted in the first three               Extent of disease        No of         No. of       Percent-
months although further radiological clearing
continued to occur upto nine months.                                            cases          cases            age
    Sputum converted in 39 cases (90%). In
25 this occurred in first 2 months, in 10 in the Moderately advanced        21          19           90.0
third month and in 4 in the four month. The
speed and incidence of sputum conversion was Far advanced                   22          20           90.0
the same in moderately advanced and in far
advanced cases. All the 39 cases maintained
the bacteriological improvement, 35 cases com-                          TABLE 3
pleted treatment for full one year, 3 cases for           Showing the adverse reactions to drugs
9 months and one for 8 months. The four
cases who responded to treatment but did not                  Total number of cases-43
complete full one year treatment did not report Nature                               No. of Percent-
for collection of drugs and could not be                                             cases       age
Drug Toxicity and side effects (Table No. 3)          Gastrointestinal

   Adverse reactions to the drugs were com-             Persistent                              2               4.4
mon but were not serious enough to need with-           Minor                                  7                15.5
drawal of the drugs except in two cases.
                                                      Neuropathy (Subjective)                   2               4:4
    A metallic taste in the mouth, anorexia,
nausea or vomiting was compLalned of by 9             Allergic                                  2               4.4
cases (19.9%). In 2 cases the symptoms were           Miscellaneous                            6                13.3
persistent and intractable and the patients
refused to continue the treatment. In the other
7 the symptoms became less or disappeared in
course of time.                                       allergy to one of the drugs. However, these
                                                      symptoms could be controlled by small doses
   Burning sensation in the palms and soles           of anti-histaminics.
and pain in the limb were compLalned by 2                 3 cases compLalned of drowsiness and
cases (4.4%). These symptoms were controlled          lethergy ; one of them was a diabetic. Another
with 10 mg. pyridoxine hydrochloride per day          2 cases compLalned of heaviness in the head.
while the anti-tubercular drugs were continued.       Gynecomastica with acne was noted in one
In no case there was objective evidence of            case. These symptoms needed re-assurance
neuropathy.                                           only.
   In 2 cases (4.4%) a transient rash and                 No case of jaundice or exfoliative dermati-
itching occurred which was attributed to              tis was noted in the present series.
                                                                         Ind. J. Tub.. Vol. XVI, No. 2
    62                                           R. K. NARANG

    Discussion                                            sputum conversion in 77% of 13 cases at 6
        In the present study 400 mg. isoniazid and            Gastrointestinal side effects were noted in
    500 mg. ethionamide was given orally in a             20% cases in the present report but except in
    single dose at bed time in middle aged and            two cases they were not troublesome enough
    elderly patients of pulmonary tuberculosis who        to need withdrawal of the drugs. Thus in
    were not previously treated with anti-tuber-          500 mg. dose daily ethionamide was very well
    cular drugs. The dose of ethionamide is               tolerated. Good tolerance was also observed
    smaller than used in the British Tuberculosis         in other series mentioned above. This is in
    Association (1961) investigation. There is a          marked contrast to the high incidence of
    good experimental support for using small             intolerance in the British Tuberculosis Associa-
    doses of ethionamide with isoniazid. Thus             tion trial (1961) of a combination of ethiona-
    Mm. Grumbach (1963) concluding on the                 mide, pyrazinamide and cycloserine. In a
    basis of experimental tuberculosis in mice            more recent study by the British Tuberculosis
    recommends 400 to 500 mg. isoniazid (corres-          Association (1968J, again a high incidence of
    ponding to 4 times the minimal effective dose)        gastrointestinal symptoms were reported. In
    with 200 to 500 ethionamide. Again RIST               this study ethionamide was combined with
    (1964) as a result of laboratory experiments          streptomycin and isoniazid. The dose of
    observed that in isoniazid-ethionamide combi-         ethionamide in both the trials was high. That
    nation isoniazid is the principal drug and            the dose of ethionamide is one of the impor-
    should be given in high doses while 500 mg.           tant factors in relation to the incidence of
    ethionamide is adequate.                              gastrointestinal side effects is also suggested by
                                                          a trial of ethionamide, isoniazid and thiaceta-
        Initially 50 cases were selected for the trial.   zone in drug resistant cases by the present
    However, 5 cases did not satisfy the protocol         author (Narang and Sarin, 1966). In this
    and were withdrawn. Another 2 cases were              investigation 750 ethionamide in two divided
    withdrawn in the first fortnight due to gastro-       doses was used and a high incidence of gastric
    intestinal intolerance to the drugs. Thus             upsets was observed. Other possibly important
    efficacy of the drugs has been analysed in 43         factors are the drug combinations and racial
    cases and side effects to the drugs in 45 cases.      differences.
        Sputum conversion was obtained in 39 of              Allergic manifestations were uncommon
    the 43 cases (Conversion rate 90%) who                and could have been due to ethionamide or
    remained in the trial sufficiently long. If all       isoniazid. Carey (1965) reports successful
    the 45 cases are included, the conversion rate        desenstisation in a case of ethionamide allergy.
    was 81.57%.
                                                              Minor side effects included drowsiness,
        There are three other reports in the lite-        lethargy, heaviness in the head, gynecomastica
    rature on the use of ethionamide-isoniazid            and acne. Drowsiness may be a manifestation
    combination in previously untreated cases.            of hypoglycemia (British Tuberculosis Associa-
    Our material, in [contrast to these reports,          tion, 1968). Hypoglycemia has been described
    consisted of middle aged and elderly patients         in diabetic patients treated with ethionamide
    only. Again, while in the present report the          (Clark and O’Hea. 1961, Somner and Brace,
    doses of ethionamide and isoniazid were               1962). Of the three patients in the present
    500 mg. and 400 mg. respectively given in a           series, who compLalned of drowsiness, one
    single dose, Lees (1964) from Glasgow used            was a diabetic. But investigations to exclude
    1 gm ethionamide with 400 mg. isoniazid,              hypoglycemia were not done.
    British Tuberculosis Association/Hong Kong
    Tuberculosis Treatment Services (1964) and                Clinical jaundice was not noted in a single
    Bhatia and Lal (1966) from Amritsar used              case. This is especially striking considering
    500 mg. ethionamide and 300 mg. isoniazid.            that the 3 of the cases in the present study
    While in the Hong Kong trial the drugs were           were known diabetics ; the diabetics and the
    given in a single dose, the Amritsar workers          alcoholics are especially prone to develop
    gave the drugs in two divided doses.                  hepatotoxicity (De Voogd, 1963). The low
                                                          incidence of icterus has also been reported by
        In the Hong Kong trial, sputum conversion         other workers. However, routine liver func-
    was obtained in 98% of cases who continued            tion tests are likely to reveal abnormality in a
    the drug for one year, overall conversion rate        higher percentage (Bhatia and Lal, 1966 ;
    was 85% including those who left off. Lees            Somner and Brace, 1967 ; British Tuberculosis
    (1964) obtained sputum conversion in all the          Association, 1968). No routine liver function
    32 cases. Bhatia and Lal (1966) noted a               tests were done in the present study.
     Ind. J. Tub , Vol. XVI, No. 2


    Some of the treatment failure cases might                       REFERENCES
have been primarily resistant to one of the
drugs. As sensitivity tests were not done, their   1.    British Tuberculosis Association       ( 1961 ):
incidence is not known. There is a very                  Tubercle, Land. 42, 269.
interesting relationship between isoniazid
resistance and ethionamide. While low degree       2.    British Tuberculosis Association/Hong Kong
isoniazid resistant bacilli are sensitive to             Tuberculosis Services (1964) : ibid, 45, 299.
ethionamide, in man there is usually a high
degree isoniazid resistance even in rapid          3.    British Tuberculosis Association (1968) : ibid.
inactivators so that ethionamide is likely to be         49, 125.
effective in such cases. Canneti (1965) and        4.    Bhatia, J. L. and Lal, H. (1966) : Indian J.
Nazaki (1964) in experiments using H37Rv                 Tuberc. 13, 57.
strain of mycobacterium tuberculosis resistant
to 50 meg per cc. of isoniazid found that the      5.    Canneti, G. (1965) : Amer. Rev. Resp. Dis.
combination of ethionamide and isoniazid had             92, 687.
higher antibacterial activity against the test
strain than ethionamide alone and observed         6.    Carey, V.C.I. (1965) : Tubercle, Land., 46, 287.
decreased resistance of resistant strain to
isoniazid. They confirmed these findings in        7.    Clark, G.B.M. and O’Hea, A.J. (1961) : Brit.
male mice.                                               Med. J., 1, 636.

Summary                                            8.    De Voogd, A. (1963) : Rev. Tuberc. 27, 935.
                                                         Abstracted Amer. Rev. Resp. Dis. 91, 158, 1965.
    The role of 500 mg ethionamide and
400 mg isoniazid, given in a single dose orally    9.    Mm. Grumbach, F. (1963): Abstr. ibid, 87, 800.
at bed time was assessed in 45 previously un-      10. Lees, A.W. (1964) : Dis. Chest. 45, 247.
treated middle aged and elderly cases of pul-
monary tuberculosis. 90% sputum conversion         11.   Narang, R.K. and Sarin, J.N. (1966) : J. Assoc.
was obtained. If those who fell out of                   Phys. India, 14, 503.
the trial due to drug intolerance the conversion
rate was 81.5%. The drugs, in the dosage           12.   Nazaki, T. (1964) : Kekkaku, 39, 27, Abstr.
given, were very well tolerated.                         Amer. Rev. Resp. Di. 91, 808, 1965.

           ACKNOWLEDGEMENT                         13.   Rist, N. (1964), Selected Papers of Royal
                                                         Netherlands Tuberculosis Association, 8, 24.
   The author acknowledges the generous
supply of ethionamide by M/s. Themis               14.   Somner, A.R. and Brace, A.A. (1967), Tuberc.
Pharmaceuticals.                                         Lond.,49, 137.

                                                                   Ind. J. Tub., Vol. XVI, No. 2
                                        B. K. KHANNA
                             (From K. G’s Medical College, Lucknow)
Introduction                                              2.4.2. According to previous treatment
                                                        the distribution of cases was as follows
    Thioacetazone has, during the last few years,       (vide table No. 2).
raised many points of controversy. While its
efficacy as tuberculostatic agent has been                2.4.3. According to various treatment
compared with that of PAS, its toxicity in vivo         schedules, the distribution of cases was as
studies has been found to be variable (Miller           follows (vide table No. 3).
Fox and Tall, 1966, Aquinas 1968 and Miller,
1968). It has been suggested that latter                                     TABLE 1
manifestations may vary with the dietary                            Final distribution of cases
habits (Miller, Fox and Tall, 1966) and race.                                        PAS      Thioacetazoue
(Miller, Fox and Tall, 1966 and Aquinas,                                             Group          Group
    We have been using Thioacetazone in             Total number of cases
                                                    (Initial)                          207          193
various combinations in our hospital for the        Cases dropped from trial             4            6
past 5 years, and have conducted a controlled
trial on the relative efficacy of thioacetazone     Reasons: Incomplete data             1              2
and PAS in the management of cases suffering
from pulmonary tuberculosis. The present                       Incorrect History         1              1
report pertains to that aspect of the problem.                 Left against advice        2             3
Material & Methods
                                                    Cases available for final
    390 cases suffering from pulmonary tuber- analysis                             203           187
culosis, admitted to Kasturba Hospital, were
studied. These cases were divided by. random                              TABLE 2
sampling into two groups—one group was                  Distribution of cases according to previous
recepient of PAS in conjunction with other                 chemotherapy received by the cases.
anti-tuberculosis drugs while the other received                   PAS Group         Thioacetazone Group
thioacetazone in place of PAS. Exact dosage
and drugs schedules are given below:             Untreated            108                      91
    All the cases at the initiation of trial had to Treated                95                      96
fulfil following criteria:
      2.1. Sputum must be positive for AFB             Total              203                     187
    (smear examination.)
       2.2. Radiological picture should be com                          TABLE 3
    patible with the diagnosis of pulmonary            Distribution of cases according to various
    tuberculosis with atleast one cavity in                      schedules of treatment.
    either infraclavicular region.                               PAS Group Thioacetazone Group
       2.3. Every case was asked in detail
    regarding the amount of drug treatment he                    SPH      PH     STH              TH
    had received in past. Those who had taken
    less than 10 days of chemotherapeutic Untreated               52       56      42              49
    treatment prior to their admission to the
    hospital were labelled as ‘untreated’ and Treated             61       34      57              39
    those who had more than 10 days’ therapy
    were labelled as ‘treated’.
                                                  Total          113       90      99              88
       2.4.1. The final distribution of cases was
    as follows (vide table No. 1).
  Ind. J. Tub., Vol. XVI, No. 2
                  ROLE OF THIOACETAZONE AND PAS IN PULMONARY TUBERCULOSIS                                         65

Schedule of Treatment                                       Chest X-ray was repeated every three
    S+T+H—Streptomycin IG IMI once a
day—Thioacetazone 150 mgms/day—INH 10                       2.7. Assessment of results were based
mgms/kg. body weight—vitamins (hitherto                   emperically as under:
referred to as STH group).
                                                          (a) Improved: Sputum conversion.
    T+H—Thioacetazone and isoniazid admi-
nistered in the same dose as above (hitherto                  Sub-Group: Marked Improvement—Sputum
referred to as TH group).                                       conversion with disappearance of cavity.
    S+P+H—Streptomycin and Isoniazid                             Moderate: Sputum conversion                    with
administered in usual dosage—PAS 10 G/day                        reduction in size of cavity.
(hitherto referred to as SPH group).
                                                                 Mild: Sputum conversion with cavity
   P+H—PAS and INH administered in same                          represented by a bullous cyst.
dose as in SPH group (hitherto referred to as
PH group).                                                (b) Stationery: No sputum conversion, chest
   After 3 months of daily injections of
Streptomycin the injections were withdrawn                (c) Deteriorated: Deterioration on radiological
and patients received only TH or PH group of                   and clinical grounds or development of
drugs.                                                         toxic reactions to the chemotherapy.
2.5. Duration of Treatment                                 Results
    Duration of therapy was 6 months in each                  Final overall results have been depicted in
case. All the cases had to stay in the hospital            Tables No. 4, 5 and 6.
during the period of trial. 5 cases who had
left the hospital prematurely had to be with-              Discussion
drawn from the present trial (vide Table
No. 1).                                                       This study relates to hospitalised cases and
                                                           extends over a period of six months’ observa-
2.6. Investigations                                        tion.
   Sputum examination for AFB (Smear                          In the hospital itself drug administration
examination by ZN technique) was done every                was done by the trained nurses who would
month. Gaffkey count was taken as a guide to               ensure regular intake of adequate dosage of
progress.                                                  drugs in their presence. While Thioacetazone
                                                      TABLE 4
                                  Overall results at the end of six months’ study.
Results                                                Groups:

                        SPH (113)               STH (99)                PH (90)             TH (88)

Improved                72(64%)                 60(61%)              56(62%)                46(52%)

     Marked:                      25(22%)                 12(12%)                 11(12%)             10(11%)
     Moderate:                42(37.5%)                   38(39%)                 26(29%)             13(15%)
     Mild                         5(4.5%)                  10(10%)                19(21%)             23(26%)
Stationary              22(18%)                (15(15%)              1102%)                 9(10%)
Deteriorated            16(14%)                 19(19%)              21(23%)                28(32%)
Expired                  2( 3%)                  2( 2%)                 2( 3%)              1(1.5%)
Therapy changed          U 1%)                   3( 3%)                  —                  4(4.5%)

                                                                             Ind. J. Tub., Vol. XVI, No.. 2
66                              B. K. KHANNA

Ind. J. Tub., Vol. XVI, No. 2

                                                   TABLE 6
                                              Toxic manifestation
                                                    SPH              STH         PH        TH
                                                    (113)            (99)       (90)       (88)

                  1.   Ototoxicity                   3                8          —        2
                     (Vestibular Damage)
                  2. Cutaneaus Rashes                —                 5         —            3
                  3. Cutaneous rashes severe
                     enough to warrant a
                     withdrawal of drugs.            —                 2         —            1
                  4. Hepatic toxicity                —                 3          1           3
                  5. G.I. Intolerance                 2                5          3           8
                  6. Peripheral Neuritis              1                2          1           1

                        1.   One case in STH group died due to severe hepatic damage
                             passing on to hepatic coma.
                        2.   One case in STH group and one in TH group developed such a
                             severe cutaneous reactions that withdrawal of therapy and
                             administration of corticosteroids had to be resorted to, in an
                             attempt to save their lives.

and isoniazid tablets were swallowed in a                   viomycin, cycloserine, pyrazinamide, ethiona-
single dose, PAS and INH were given in 2                    mide, kenamycin, ethambutal etc.). Further
divided doses administered after meals. Thus,               tolerance to these drugs is very poor. There-
the problem of drug default was almost com-                 fore, irrespective of the drug resistance pattern
pletely eliminated. However, since the bulk of              of the tubercle bacilli excreted by the patient,
PAS and Isoniazid was quite different from                  an attempt was made to evaluate the efficacy
that of Thioacetazone and Isoniazid, it was                 of Thioacetazone in combination with Isoniazid
not possible to perform a double blind trial on             alone or in conjunction with Streptomycin.
the subject.                                                The results in the irregularly treated group of
                                                            the cases are disappointing and are certainly
    A glance through table Nos. 4, 5 and 6                  not better than PH or SPH groups.
reveals certain outstanding features. These can
be summarised as under:                                        4.2. The tolerance to thioacetazone was
                                                            poorer as compared to that of PAS. Both
   4.1. Clinical response to Isoniazid and                  major and minor toxic reactions were met with
Thioacetazone combination was poorer as                     much more frequently in the former series.
compared to that of Isoniazid and PAS group.
This was especially true for those cases who                  4.2.1. Jaundice appeared during thioaceta-
had not received previous treatment with anti-            zone therapy in six cases (2 cases in untreated
tuberculosis drugs.                                       group and 4 in treated group) as compared to
                                                          that of one (belonging to untreated group)
    Culture and sensitivity studies on tubercle           case in PH group. In one case of the former
bacilli were not done although the facilities for         group, the patient passed on to hepatic coma
the same did exist in our hospital. During the            and could not be saved. However, in remain-
trial our attempts were to create condition               ing five cases belonging to TH group thioace-
which can be reproduced in any hospital. Most             tazone in test dosage (1 mgm.) was again
of the cases getting admitted to our hospital             started after the remission of jaundice. There
are those who have been grossly (and irregu-              was no recurrence of jaundice. Thereafter, full
larly) treated in the past without deriving any           dose of thioacetazone was instituted. This led
benefit. They have meagre resources at their              us to conclude that jaundice in these cases
command and may not be able to afford                     could have been due to some other cause (e.g
second line of anti-tuberculosis drugs (e.g.              infective hepatitis or homologous serum
                                                                            Ind. J. Tub., Vol. XVI, No. 2
                                         B. K. KHANNA

jaundice). However, its predominance in the         study on thioacetazone (Miller et al, 1966) has
thioacetazone group might be regarded to            already emphasised these points and has
indicate a casual relationship. It is also likely   further emphasised that before embarking on a
that hepatotoxicity due to thioacetazone might      mass scale use of this drug on a domiciliary
be due to cumulative toxic reactions of the         basis, its tolerance in that particular commu-
drug and it might not have re-manifested itself     nity must be ascertained. Our study has
during the remaining period of hospitalisation      demonstrated that thioacetazone is not so well
of the patients.                                    tolerated as PAS atleast by the residents of
                                                    Utter Pradesh, and that it is liable to lead to
     4.2.2. Severe expholiative dermatitis was      serious toxic reactions which may occasionally
met with in 3 cases in the thioacetazone group      be fatal.
(all belonging to ‘treated’ group). In two cases
withdrawal of drug and symptomatic therapy          Summary
failed to produce any improvement. 60 mgms
Prednisolone per day had to be instituted to            390 cases suffering from pulmonary tuber-
save their lives. These cases were later with       culosis admitted to Kasturba Tuberculosis
drawn from the group. Reinstitution of isoni-       Hospital were divided into four groups by
azid and streptomycin was not followed by           random sampling. 203 cases received PAS
any cutaneous reaction in this group of cases.      (10 gm/day) and isoniazid (400 mgms/day), 113
However, we avoided further use of thioace          received streptomycin (1 G IMI7 once a day)
tazone in them.                                     for first 3 months of observation in addition.
                                                    187 cases received Thioacetazone (150 mgms/
    4.2.3. Thioacetazone group of cases suffe-      day) instead of PAS along with isoniazid (in
red from toxic reactions to streptomycin on 8th     usual dosage), 99 received streptomycin also.
nerve more frequently as compared to that of        Our study extended over a period of six
PAS group.                                          months and all along these cases were hospi-
                                                    talised. It was noted that the response to
    Potentiation of ototoxic reaction of strep-     thioacetazone was inferior to that of PAS
tomycin by thioacetazone (not by isoniazid,         particularly in those cases who had not recei-
because it was a common drug in both the            ved chemotherapy in past. Further, the
groups) permits us to conclude that combina-        tolerance to thioacetazone was found to be
tion of thioacetazone and streptomycin should       poorer than that of PAS.
be avoided in presence of obvious renal damage
and in persons beyond the age of 40 years.                       ACKNOWLEDGEMENTS
Of 8 cases in the STH group who had developed
this toxicity 5 were beyond 40 years of age.           The author is grateful to Drs. J. Nath and
Two cases receiving thioacetazone and isonia-       S.P. Misra for their cooperation in the trial.
zid alone developed ototoxic reactions (vesti-      His grateful thanks are also due to M/s.
bular damage). This implies that thioacetazone      Unichem Laboratories for the liberal donations
besides potentiating the vestibular damage due      of Unithiben VF tablets containing Thioace-
to streptomycin, could by itself damage the         tazone, isoniazid, antihistamine and vitamins.
vestibular system independently: although the
number of cases is too small to arrive at a                              REFERENCES
definite conclusion (Deshmukh and Master,
1962, Miller, Fox and Tall, 1966 and Miller,            1.   Aquinas, M. (1968) Side Effects and Toxicity to
                                                             Thioacetazone and Isoniazid, Finding in A
1968).                                                       Hongkong Tuberculosis Treatment Service/
                                                             British Medical Research Council Investigation.
    The study permits us to conclude that on                 Tubercle (Land.), Supplement to Vol. 49; 56.
clinical grounds thioacetazone is inferior to
that of PAS and is more toxic than PAS (with            2. Deshmukh, M.D. and Master, T.B. (1962)
                                                           Thioacetazone and Isoniazid in the Treatment
reference to both minor and major toxic                    of Pulmonary Tuberculosis J. Indian Med., Prof.
reactions).                                                9, 4273.

    This observation, however, may not apply            3. Miller, A.B., Fox, W. and Tall, R. (1966), An
universally in all the cases of pulmonary tuber-           International Cooperative Investigation into
                                                           Thioacetazone (Thioacetazone) side effects.
culosis because it has been demonstrated that              Tubercle (Land.), 47; 33.
tolerance to thioacetazone may depend on race
(Aquinas, 1969), nutritional status of the host         4. Miller, A.B. Thioacetazone Toxicity: A General
and many other factors. The international                  Review. Tubercle (Land.), Supplement 49; 54.

 Ind. J, Tub., Vol. XVI, No. 2
                                       NEWS & NOTE
Annual Meetings                                       Shri B.M. Cariappa, the Secretary-General,
                                                  also visited Goa and attended a meeting of the
    The Thirteeth Annual General Meeting of       Executive Committee of Goa Association and
the Tuberculosis Association of India was held    addressed the Rotarians and Care-Committees
on 18th April at 11.30 A.M. in the Conference     in Panjim.
Hall of the Association. Dr. S. Chandra-sekhar,
the President of the Association, presided. The   West Bengal Conference
Chairman of the Association presented the
report on the working of the Association              The Bengal Tuberculosis Association held
during 1968 and the Honorary Treasurer            the 2nd West Bengal TB Conference from 12th
presented the accounts. The meeting elected       to 14th April, 1969 in Calcutta. The confe-
members to the Central Committee as provided      rence included three symposia, and a few origi-
for in the rules.                                 nal papers were also presented.

    The Conference of the Secretaries of the          On this occasion, the Association brought
State TB Associations and Seal Sale Organisa-     out an attractive Souvenir containing useful
stions in India was held in the Conference Hall   information on the development of tuberculosis
of Association at 3.00 P.M. on 18th April and     services in the State. The Association also
the Technical Committee of the Association        inaugurated at this time a special chest
meet on 19th April.                               clinic for children, the first of its kind in India
                                                  containing advanced laboratory facilities for 42
VII Maharashtra Conference                        affiliated chest clinics. The three-storeyed
                                                  building was built at a cost of Rs. 2,25,000.
   The      Maharashtra      State     Anti-TB
Association organised a two-day State TB and      Conference in Assam
Chest Diseases Workers Conference in
Bombay from 22nd to 24th March, 1969. The            The TB Association of Assam will be hold-
Conference which was inaugurated by Dr. P.V.      ing a Seminar on Tuberculosis shortly. The
Cherian, the Governor of Maharashtra was          Seminar is likely to be attended by Dr. P.K.
addressed by Smt. Pratibha D. Patil, Deputy       Duraiswamy, Director General of Health
Minister for Public Health and Prohibition. Dr.   Services, and Shri B.M. Cariappa, Secretary-
P.K. Duraiswamy, Director General of Health       General, Tuberculosis Association of India.
Services and Chairman of the Tuberculosis         Award to Dr. R. Viswanathan
Association of India, also addressed the confe-
rence.                                                Dr. R. Viswanathan, Emeritus Scientist,
                                                  Vallabhbhai Patel Chest Institute, University
    Shri B.M. Cariappa, Secretary-General,        of Delhi, Delhi, has been awarded the Eugenic
Tuberculosis Associations of India, was the       Morathe Prize by Academia De Lincie of Italy,
President of the Conference. Shri Cariappa’s      for outstanding contribution in the field of
address covered the role of voluntary TB Asso-    Tuberculosis and Chest Diseases. The prize
ciations in India with special reference to       has been awarded only to three other distingui-
Maharashtra.                                      shed scientists so far in the world. Dr.
                                                  Viswanathan is the first non-Italian to receive
    Discussions included ‘Control of Tuberculo-   the Award, the value of which is two million
sis in rural areas’ in which Dr. B.B. Yodh and    Liras.
P.A. Deshmukh participated. Dr. M.D. Desh-
mukh and Dr. J.C. Kothari took part in the        Seal Sale Award—1969
discussion on ‘Place of Thiacetazone in treat-        The 1969 Trophy for the highest Seal Sale
ment of Pulmonary Tuberculosis’. In another       collections, was awarded to the Tamilnadu
discussion on ‘Tuberculosis in Children’ Dr.      TB Association. The Trophy was presented
M.M. Wagle and Dr. M. Asher participated.         to the Association at the time of the Annual
                                                  General Meeting of the Association held on
   The Conference concluded with a Meeting        18th April, 1969.
of the Secretaries of District Associations in
Maharashtra.                                      Proceedings of the XXIII TB Conference
    On the occasion of the conference the             Copies of the Proceedings of the Twenty-
Maharashtra Association brought out an inte-      third Conference held in Bombay in 1968 are
resting handbook on Tuberculosis.
                                                                 Ind. J. Tub., Vol. XVI, No. 2
70                                         NEWS & NOTE

available for sale from the Tuberculosis Asso-       in different disciplines of Medical sciences on
ciation of India, 3-Red Cross Road, New              an All India basis with a view to admit candi-
Delhi-1. The price per copy is Rs. 23/- plus         dates to the Membership of the Academy. The
postage.                                             next examination will be held in July, 1969 in
                                                     Delhi only. Application forms can be obtained
Chest Diseases’ Prize Award                          from the Executive Director, Indian Academy
    The Indian Association for Chest Diseases        of Medical Sciences, C-II/2, Medical Institute
has instituted a cash prize of Rs. 200 to be         Campus, Ansari Nagar, New Delhi-16.
given to the author of the best article published
during the previous year either in Indian or             In another announcement, the Academy
foreign Journal on any subject in the speciality     has also invited young scientists engaged in bio-
of chest diseases. The prize is open to only         medical research to participate in the Scientific
those who are under the age of 40 years. The         session of its annual meeting to be held in
work on which the article is based must have
been conducted in India. Details can be had          December, 1969 and is open to scientists of the
from the Secretary, Indian Association for           age of forty and below. Selected scientists
Chest Diseases, Silver Jubilee TB Hospital,          will be paid travelling and daily allowances for
Kingsway, Delhi-9 by 31.7.1969.                      attending the Scientific session of the Academy
Indian Academy of Medical Sciences                   and for presenting their papers. The papers
   The Indian Academy of Medical Sciences            should be submitted to the Executive Director
has been conducting postgraduate examinations        not later than 15th September, 1969.

       A FREAK accident, which resulted in the death of one African miner
and the poisoning of 199 others, occurred at the Doornfontein Gold Mine,
near Carletonville, early in November.
        Instead of the usual purgative administered at their dressing stations
they received, in error, doses of isoniazid or INH, the well-known effective
drug used in TB treatment, which in therapeutic doses is harmless. They
developed stomach cramps and started vomiting and were taken to hospital
where one of them died later in the day. The others recovered.
        The mine concerned is one of those which has in the past six years
been adding, with the consent of the mine workers, prophylactic INH to their
daily ration of marewu, a non-alcoholic maize drink popular among Africans.
This experimental scheme, reported in SANTA News (September, 1968) has
shown an 80 per cent decrease in TB incidence among the 41,000 African
miners who have taken part.
                                                    From SANTA NEWS, December, 1968

 Ind. J. Tub., Vol. XVI, No. 2
                          UPHILL ANTI-T.B. FIGHT
      A CERTAIN COMPLACENCY is discernible of late in the public atti-
tude to such dread scourges as tuberculosis. The development of powerful anti-
microbial drugs and the perfecting of effective and yet comparatively low- cost
domiciliary treatment for sufferers from this disease (as against the expen-
sive medical care in sanatoria) may have something to do with it. But the
figures of the high incidence of this killer (7 to 8 million cases) and deaths
(half a million) from it every year and the indequate facilities for its control
available, referred to by Dr. S. Chandrasekhar, Union Minister of State for
Health, at the 30th annual meeting of the Tuberculosis Association of India
should serve to warn against any relaxation in the war on this old and insidious
enemy. The plan of attack leans heavily on having at least one Control
Centre in each district from which radiate teams to diagnose and treat the
victims in the area. Only 171 of the 336 districts in India have such centres
and each of these control points can deal with only about 4,000 cases. The
inexorable arithmetic of it all is that as many as 5 to 6 million T.B sufferers go
without proper medical help. And coming from the Union Minister of Health
himself, this confession of inadequacy is indeed as alarming as it is authentic.
       The obvious remedy is to quicken the tempo of enlargement of the clinics
and control centres. But the hurdles that have slowed down the process in
the past—lack of trained workers, funds, equipment and so on—are still there.
Fortunately, the voluntary T.B. Association of India has a wider network of
district branches, covering 207, than the official agency. Between these bran
ches and private doctors, the general practitioners practising in the area, much
may be done to fill the gap in more organised facilities. Dr. P.K. Duraiswami,
Chairman of the Association, has suggested the strengthening of the curriculum
of medical under-graduates, to include more expertise on the treatment of this
disease to help even G. Ps. to tackle T.B. patients with competence. Even as it
is, if every general practitioner refers suspected cases to the nearest clinic and
undertakes the supervision of the follow-up treatment and the education of
their contacts, they would be supplementing the organised network of
control centres. The Association which has been doing yeoman service to
publicise the perils of T.B. and harness public opinion to fight it may add more
sinews to its programme, if it can enlist both women’s organisations and the
private medical practitioners in its work to a much larger extent than now.
                                              (Editorial in Hindu of April 21, 1969)

                                                      Ind. J. Tub., Vol. XVI, No. 2
                  The Indian Journal of Tuberculosis

 Vol. XVI                                 April 1969                                  Abst. No. 2

Sensitivity to Thiacetazone of Myco-Bacterium         Of these 402 children, active tuberculosis
   Tuberculosis Isolated in Algiers Practical      was in 51 (12.5%) as shown radiologically and
   Deductions;                                     bacteriologically.
J. Grosset; F. Rodriguez; M. Benhassine, P.            The Heaf test was positive in only 11 of
Ghault and D. Larbaoui, Tubercle, Supplement,      these children and the intradermal test using
Vol. 49, March, 1968.                              100 tuberculin units was positive in a further
                                                   18 children. This confirms previous findings
    There is, no corelation between ‘natural’      that tuberculin sensitivity is impaired in
sensititivity to thiacetazone and ‘natural’        malnourished children and suggest that a higher
sensitivity to ethionamide. However there is Co-   dose of tuberculin is more likely to elicit a
relation between acquired resistance to ethio-     positive response.
namide and resistance to thiacetazone. There
is however systematic cross resistance between                                               H.B.D.
the two drugs.
                                                   Streptomycin Plus Thiacetazone (Thioacetazone)
                                         H.B.D.        Compared with Streptomycin Plus P.A.S.
                                                       and with Isoniazid Plus Thiacetazone in
Natural Sensitivity of M. Tuberculosis to              the Treatment of Pulmonary Tuberculosis
   Thiacetazone.                                       in Rhodesia.
D.A. Mitchison, Tubercle, Supplement, Vol 49       L. Briggs et-al. R. W. Raddle, and Wallace Fox
March 1968.                                        et-al. Tubercle, Land. (1968), 49, 48.
   1 . Efficacy of thiacetazone plus isoniazid         220 patients were allocated at random to
       varies from one area of the world to        three treatment regimens.
   2.   Preliminary control trials should be
        carried out when the use of this combi-      Thiacetazone 150 mgm plus isoniazid 300
        nation is envisaged on a major scale.      mgm daily in a single tablet.
   3.   There is no association between the        S.P.
        results of pretreatment thiacetazone
        sensitivity tests and the response to          Streptomycin sulphate 1 gm intramuscu-
        treatment.                                 larly plus sodium PAS 15 Gm. daily in three
   4.   The routine use of such sensitivity test
        is un-necessary when this combination      S.T.
        is widely used.
                                                       Streptomycin sulphate 1 gm. intra muscu-
                                         H.B.D.    larly plus thiacetazone 150 mgm daily in a
                                                   single tablet. All patients were treated in hos-
Tuberculin Test in Children with Malnutrition      pital for six months. There were 171 (58 TH,
                                                   55 SP, 58 ST) patients who complied with
Aune V.C. Lloyd, Brit Med. Jur. 31st Aug. 1968.    clinical criteria for admission and who had
                                                   strains of tubercle bacilli sensitive to isoniazid
    In 402 children with severe malnutrition,      and streptomycin. Ten patients died, five (two
Tuberculin test with Heaf’s multiple puncture      SH, two SP, one ST) from active tuberculosis,
method as well as intradermal test with varying    three (one SP, two ST) from non tuberculous
strength of old tuberculin were carried out        causes but with active tuberculosis and two
 Ind. J. Tub., Vol. XVI, No. 2
6                                              ABSTRACTS

(both TH) from possible drug toxicity with            Blood Levels of Isoniazid and of Its Methane
active tuberculosis. The sputum was negative             Sulphonate Derivative in Rapid and Slow
on both cultures at six months in 72% of TH,             Inactivators After Oral Administration.
82% of the SP and 33% of the ST patients. At
three months none (0%) of the 53 SP and 20            Aldo Baronti and Nella Manfredi, Tubercle,
(37%) of the 54 ST patients were excreting            Lond., (1968), 49, 104.
streptomycin resistant organism (P<0.001). At
six months isoniazid resistant strains were              Blood levels after oral administration of
obtained from 13% of 54 TH patients and 8%            isoniazid and its methane sulphonate derivative
of 53 SP patients had culture with an RR of 4         (Methaniazid) were compared in a group of 20
or more of P.A.S.                                     subjects consisting of 10 rapid and 10 slow
    At six months 72% of 58 TH, 76% of 55
SP and 26% of 57 ST patients had favourable              The two drugs were administered orally at a
response classified mainly on bacteriological         dose of 5 mgm/Kgm calculated as isoniazid,
grounds. The difference between the ST and            blood samples were drawn at three, six and
each of the other two regimens were statistically     nine hours and assayed with the vertical diffu-
highly significant (P>0.0001). Cutaneous hyper        sion method using Mycobactrium Tuberculosis
sensitivity occurred in 9% of the TH, of 10%          H 37 R as test organism.
of the SP and 10% of the ST patients. It was
most severe in TH patients. Jaundice occurred             The blood levels reached after administra-
in one patient in each of the three series and        tion of methaniazid were significantly higher
dizziness was recorded only in the ST patients,       than those obtained with isoniazid (PL < 0.001)
occurring in 11%.                                     in slow inactivators the difference of blood
                                                      levels obtained with two drugs did not reach a
   It is concluded that ST regimen was marke-         significant level (0.10> P 70.05).
dly inferior. The SP and TH regimens were of                                                  H.B.D.
similar effectivness, the latter being an effective
oral regimen.                                         Ethambutol Treatment of Tuberculosis in a
                                           H.B.D.        Controlled Trial
Aspergillus in Persistent Lung Cavities After             Francis O. Segatra, Victor Lorian and David
   Tuberculosis                                       S. Sherman Scand. J. Resp. Dis : 493, 202.
A report from the Research Committee of                   The efficiency of ethambutol in combination
the British Tuberculosis Association, Tubercle,       with INH and PAS in previously untreated
Land., (1968), 49, 1.                                 cases has been evaluated in a controlled trial.
                                                      After excluding those who did not complete
    Of 544 patients with persistent cavities of       3 months’ treatment, there were 47 patients
2.5 Cm. or more in diameter, 134 (25%) had            in the ethambutol group and 20 in the control
a positive precipitin test. In 59 (11%) radio-        group. Nearly 10% of the strains isolated
graphs showed typical appearances compatible          from each group of the patients showed primary
with a aspergilloma and precipitin. A further         resistance. The relief from clinical symptoms,
19 (4%) had less typical but highly suggestive        radiological change and sputum conversion was
appearances and precipitines. In most of these        marginally better in the control group. Further,
the precipitine test was strongly positive whilst     the patients in the control group achieved
the result was weaker in those without such           conversion in less time than the patients in the
radiographic evidence. The maximum preva-             ethambutol group. One patient in the 20 in
lence of aspergillus infections occurred in those     the control group developed acquired resistance
with cavitated tuberculosis of seven to 11 years      to INH as compared with 9 of the 47 in the
duration and it became constant at a some-            ethambutol group.
what lower level in those with longer standing
disease.                                                 Three patients in the control group deve-
                                                      loped severe intolerance to PAS and had to be
    The affected patients had larger cavities and     withdrawn from the study as against only one
cavities with thicker walls showed more pleural       patient who developed jaundice in the 3rd
thickening and had more cough and were fre-           week of treatment in the ethambutol group
quent recent haemoptysis. Five patients (1%)          and had to be withdrawn. No visual distur-
without precipitins were found to have radio-         bances were observed.
graphs typical of a mycetoma,
                                           H.B.D.                                               S.P.P.

                                                                    Ind. J, Tub., Vol. XVI, No, 2

Ethambutol in Initial Treatment                          The decrease in visual acuity was no more
                                                      in patients treated with ethambutol than in
   Adil Sokmensuer, Transactions of the 27th          others.
VA-Armed Forces, Pulmonary Diseases Research                                                    S.P.P.
Conference ; 1968, 3.
                                                      Ethambutol and Visual Acuity
    Twenty three hospitals in United States co-
operated to determine the effectiveness as well       Rae S. Newman, Transactions of the 27th VA-
as the toxicity of ethambutol as a substi-            Armed Forces, Pulmonary Diseases Research
tute for PAS in initial treatment of                  Conference; 1968, 4.
pulmonary tuberculosis. Some of the patients
included in the study in the beginning                   The visual acuity in 2 groups of patients,
were given 6 mg per kg. of ethambutol but             one given a dose of ethambutol 6 mg per kg.
subsequently the dose was increased to 15 mg          and the other 16 mg per kg. body weight has
per kg. body weight. INH with low dose                been compared in 1,219 patients. The decrease
ethambutol was as effective as INH and PAS            in visual acuity was no more frequent in high
in reversing infectiousness for the first 12 weeks,   dose group than in the low dose group.
but thereafter some patients in the former group
showed bacteriological reversions. In the case                                                   S.P.P.
of high dose ethambutol group, sputum con-
version throughout the trial period was equal         The combined use of capreomycin and
to INH-PAS group and the bacilli in no case             ethambutol   in    re-treatment of
developed resistance to INH. Adverse reactions          pulmonary tuberculosis
severe enough to warrant withdrawal from the
drug schedule used, were seven times more             Imasato Donomae: Amer. Rev. Resp. Dis.; 1968,
with PAS than with ethambutol.                        98,699.
                                             S.P.P.       Capreomycin and ethambutol were given
                                                      for one year to 89 patients who underwent re-
Ethambutol in the Re-treatment of                     treatment for cavitary pulmonary tuberculosis
   Pulmonary Tuberculosis                             and were excreting bacilli resistant to the
                                                      standard drugs. At 6 months, the cultures were
Hugh Kelly, Transactions of the 27th VA-              negative in 75% whereas in the remaining 25% a
Armed Forces, Pulmonary Diseases Research             gradual increase in the incidence of resistant
Conference ; 1968, 4.                                 strains was seen with continuation of treatment.
                                                          Side effects of capreomycin viz difficulty in
    Ninteen hospitals in United States partici-       hearing, tinnitus and injection pain were re-
pated in a trial to test the effectiveness of         ported by 7 patients though the symptoms were
ethambutal used in triple drug combination            severe enough to require withdrawal of drug
for re-treatment of pulmonary tuberculosis. All       in 3 cases only. The decline in visual acuity,
patients had received antimicrobial treatment         abnormality in visual fields and eye strain
for at least 6 months prior to this trial. The        occurred in 6 patients but ethambutol had to
drug regimens were used comprising of INH             be withdrawn only in one case.
and various combinations of the second line
drugs. Nine of the ten regimens included                  Because of sclerotic nature of the lesion,
ethambutol also. Two hundred and seventy              radiological regression of lesions was observed
seven patients completed the treatment for            in 27.7% of the patients at 12 months. Slight
a stipulated period of 16 weeks. Eighty five          to moderate decrease in the size of the cavity
percent of these patients were excreting bacilli      was noticed in 36.3% of the patients. Closure
resistant to INH. The sputum conversion rate          of cavities was obtained in 13.7% at 12 months
was 75%- The conversion rate showed                   treatment.
no significant difference in the various
regimens. Severe intolerance to ethambutol                                                      S.P.P.
warranting withdrawal of the drug appeared in
6 out of 203 patients receiving this drug.            The antimicrobacterial activity of Rifampin
Capreomycin was given to 44 patients, and
none of these had any severe reaction. The            Gladys L. Hobby, Tulita F. Lenert. Amer. Rev.
toxic reactions to the other second line drugs        Resp. Dis., 1968, 97, 713.
used in the trial were fairly frequent. Ethiona-
mide had to be withdrawn in 13% and cyclo-              A series of experiments were performed to
serine in 26%.                                        compare the in vitro and in vivo activity of
 Ind. J. Tub., Vol. XVI, No. 2
 8                                             ABSTRACTS

rifampin with that of INH. The data suggest          chemotherapy. The total duration of treatment
that rifampin is approximately one half as           was at least 18 months. Three drugs were
active as INH against INH-sensitive strains,         used during the stay” in the hospital, one of
both in vitro and in vivo, but is active at least    which was INH, streptomycin ethionamide or
in vitro against INH-resistant strains.              pyrazinamide but the bacilli had to be fully
                                          S.P.P.     sensitive against all drugs used. During the
                                                     ambulatory treatment, only two drugs were
Re-treatment of patients with isoniazid-
  resistant tuberculosis                                 Sensitivity tests were available for 56
                                                     patients, out of which 48 were resistant to one
D.A. Fischer, William Lester, William E. Dye         or two of the 3 standard drugs (viz INH
and Thomas S. Moulding. Amer. Rev. Resp. Dis.;       streptomycin and PAS) and 8 were resistant to
1968, 97, 392.                                       all three. Total cases resistant to INH were
                                                     45, to streptomycin 28 and to PAS 19. Of the
     The results of treatment with various com-      45 strains resistant to INH, 15 were fully viru-
 binations of second lines drugs and follow up       lent and in the remaining 30, the virulence was
 in 146 patients with INH resistant bacilli have     attenuated.
 been analysed. All patients were treated from
 1960 to 1962, with a medium duration of 46               Out of the 69 chronic excretors, only 62
 months follow up. After 120 days of treat- took drugs over 3 months. Of the remaining
 ment, the sputum of 122 (83.5%) became 7, 4 died from a serious concurrent disease and
 negative. The median time for conversion was 3 died from Tuberculosis within 3 months.
 47th day of chemotherapy. There were 27 There were 25 more deaths up to the end of the
 deaths up to January, 1966 and there were only study. Of the 37 patients surviving on 31st
 7 survivors who failed to respond to treatment. March, 1967, 32 were converted and only 5
 Thirty patients (20.5%) experienced bacterio- were still infectious. If deaths after 3 months
 logical relapse during the period of observa- are included, the sputum conversion was
 tion. Relapse occurred at a median time of obtained in 66%. Out of the 25 deaths
 12 months after start of treatment. Significant amongst those who had been treated for more
 toxic reactions were encountered in 42% of the than 3 months, 9 were converted at the time of
 patients and appeared after a median duration death.
 of more than 60 days of treatment with any
 specific drug. Of the surviving patients whose          There were 104 family contacts, of these 69
 status was known in January 1966, 88% re- chronic excretors and they were also kept
 mained consistently non-infectious.                 under serveillance. Two children, both BCG
                                                     vaccinated earlier, developed bacillary disease
                                              S.P.P. during the period of observation. In one of
                                                     them the bacilli were resistant to INH and in
                                                     the second the bacilli were sensitive to all three
The Problem of the Chronic Excretor of               drugs. None of the contacts over the age of
     Tubercle Bacilli                                15 developed tuberculosis. Although the role
                                                     of these chronic excretors in the dissemination
K. Styblo, A. Kubik, M. Langerova, E. Muthu of infection among general population cannot
Skova and K. Moravkova. Scand. J. Resp. Dis.; be estimated, the authors are of the opinion
1968, 49:3, 236.                                     that they did not influence the incidence of
                                                     primary drug resistance in subsequent years
    The management of chronic excretors of in the community to any appreciable extent.
tubercle bacilli in the district of Kolin, Czecho-
slovakia, with a population of 100,000 has                                                      S.P.P.
been studied. A person who had been excret-
ing tubercle bacilli persistently for a period of Primary Tuberculosis in Children
2 years or more was defined as ‘chronic ex-
cretor’. There were 53 such patients on 1st Morris Steiner, Raymond Zimmerman, Byung
October, 1960 when the study started and 16 Hak Park, Sudheer R. Shirall and Harry
more patients qualifying for the definition were Schmidt. Amer. Rev. Resp. Dis,; 1968, 98, 201.
added up to the end of the study on 31st
March, 1967.                                             Of the 52 strains of M. Tuberculosis
                                                     isolated from children with primary disease, 3
    All these patients were kept in the hospital strains were significantly resistant to INH and
for 9 to 15 months, followed by ambulatory 3 to streptomycin. The same prevalence of
                                                                    Ind. J. Tub., Vol. XVI, No; 2
                                              ABSTRACTS                                        9

drug resistant strains was found in strains          Effect of ultra violet irradiation on the acid
isolated from the corresponding source cases.           fastness of drug-resistant mutants of tubercle
                                                        with special reference to the virulence of
    All 137 strains of M. Tuberculosis isolated         isoniazid-resistant strains
from all children, 9 were significantly resistant
to INH compared with 6 of the 79 strains             Toy oho Murohashi and Konosuke Yoshida.
from the source cases. The prevalence of             Amer. Rev. Resp. Dis.; 1968, 97, 283.
streptomycin and PAS resistant strains was
also similar. The study indicates that the level         There is a high degree of co-relation bet-
of primary drug resistant infections among           ween the degree of INH resistance, the viru-
children in the community under surveillance         lence of the resistant bacilli and the effect of
is closely comparable to the level of drug           ultra violet irradiation effect on acid-fastness
resistance among the adults” from whom the           by a much shorter period of ultra violet
tuberculosis infection is acquired.                  irradiation than the virulent strains and their
                                                     streptomycin and PAS resistant mutants. The
                                            S.P.P.   factor that is suspected to be concerned appears
                                                     to be the cell wall structure of the bacillus
Spread of drug-resistant tubercle bacilli            which becomes thinner in accordance with the
                                                     degree of resistance to INH.
E. Brander, K. Aho & J. Patiala. Amer. Rev.                                                     S.P.P.
Resp. Dis.; 1968, 98, 407.
                                                     Pseudocavities of the Lung
   The source infection was studied in 50
adult cases of pulmonary tuberculosis caused         Sanford E. Rabushka & Hiram T. Langs ton.
by primarily drug-resistant bacilli of human         Amer. Rev. Resp. Dis.; 1968, 97, 644.
type. The patients were relatively young, with
a medium age of 25 years as compared to 41               The concept of pseudocavities in the lung
                                                     has been discussed. The high lipid content of
years in the case of all newly diagnosed cases.      caseous material in the centre of round foci
Seven of the strains were resistant to all the       often gives a shadow, indistinguishable radio-
three major drugs, 3 to two drugs and the            logically from the shadow of a real cavity.
remaining 40 to one drug only. With the              This concept has been proved through radiolo-
exception of two catalase—negative strains, the      gical studies with ‘mock’ lesions attached to the
bacilli gave rise to progressive disease in the      chest of volunteers before radiography.
guinea pigs.
                                                     Singing and the Dissemination of tuberculosis
   A positive source of infection was found in
7 of the 11 patients more than 45 years old.         Robert G. London. Rena Marie Roberts, Amar.
Only 3 of the 23 patients less than 25 years of      Rev. Resp. Dis.; 1968, 98, 297.
age disclosed a possible source of infection
whereas 13 gave the history of old contact.              The risk of droplet infection through singing
                                                     has been studied. Fewer droplets were ex-
    The results indicated that the disease in the    pelled during singing than during talking, but
                                                     a higher proportion of them were in the
majority of the young patients originated from       smaller size range. The percentage of droplets
the old primary infection caused by drug             still airborne as droplet nuclei after a 30,
resistant bacilli. The study also demonstrates       minute settling period were 35.7, 6.4 and
usefulness of drug resistance as a microbial         48.9 for singing, talking and coughing res-
                                                     pectively. The very high proportion of smaller
marker in the epidemiological study of tuber-        droplets expelled during singing would tend to
culosis.                                             indicate high risk of infection through this
                                            S.P.P.                                               S.P.P.

 Ind. J. Tub., Vol. XVI, No. 2

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